Template-fixed beta-hairpin peptidomimetics with protease inhibitory activity

ABSTRACT

wherein Z is a chain of 11 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or Pro(4NHCOPhe), or of certain types which, as the remaining symbols in the above formula, are defined in the description and the claims, and salts thereof, have the property to inhibit proteases, in particular serine proteases, especially Cathepsin G or Elastase or Tryptase. These β-hairpin peptidomimetics can be manufactured by processes which are based on a mixed solid- and solution phase synthetic strategy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No. 15/170,233, filed on Jun. 1, 2016, which in turn is acontinuation application of U.S. patent application Ser. No. 14/100,878,filed on Dec. 9, 2013, which in turn is a divisional application of U.S.patent application Ser. No. 11/816,589, filed on Oct. 5, 2007, now U.S.Pat. No. 8,658,604, issued Feb. 25, 2014, which application is theNational Stage of International Application No. PCT/EP2005/001622, filedFeb. 17, 2005, the entire contents of each of which is incorporated byreference herein.

FIELD OF THE INVENTION

The present invention provides template-fixed β-hairpin peptidomimeticsincorporating a template-fixed chain of 11 α-amino acid residues which,depending on their position in the chain, are Gly, or Pro, orPro(4NHCOPhe), or are of certain types, as defined hereinbelow. Thesetemplate-fixed β-hairpin peptidomimetics are useful as inhibitors ofprotease enzymes. They are especially valuable as inhibitors of variousserine proteases such as human cathepsin G, elastase, or tryptase. Inaddition the present invention provides an efficient process by whichthese compounds can, if desired, be made in library-format.

The β-hairpin peptidomimetics of the invention show improved efficacy,oral bioavailability, improved half-life and most importantly a highselectivity ratio among different serine proteases which depends on theproper choice of certain types of α-amino acid residues and theirposition in said chain. In addition these β-hairpin peptidomimetics showa low hemolysis on red blood cells and low cytotoxicity.

BACKGROUND OF THE INVENTION

Inhibitors of proteases are emerging with promising therapeutic uses inthe treatment of diseases such as cancers (R. P. Beckett, A. Davidson,A. H. Drummond, M. Whittaker, Drug Disc. Today 1996, 1, 16-26; L. L.Johnson, R. Dyer, D. J. Hupe, Curr. Opin. Chem. Biol. 1998, 2, 466-71;D. Leung, G. Abbenante, and D. P. Fairlie, J. Med. Chem. 2000, 43,305-341, T. Rockway, Expert Opin. Ther. Patents 2003, 13, 773-786),parasitic, fungal, and viral infections [e.g. schistosomiasis (M. M.Becker, S. A. Harrop, J. P. Dalton, B. H. Kalinna, D. P. McManus, D. P.Brindley, J. Biol. Chem. 1995, 270, 24496-501); C. albicans (C.Abad-Zapetero, R. Goldman, S. W. Muchmore, C. Hutchins, K. Stewart, J.Navaza, C. D. Payne, T. L. Ray, Protein Sci. 1996, 5, 640-52), HIV (A.Wlodawer, J. W. Erickson, Annu. Rev. Biochem. 1993, 62, 543-85; P. L.Darke, J. R. Huff, Adv. Phannacol. 1994, 5, 399-454), hepatitis (J. L.Kim, K. A. Morgenstern, C. Lin, T. Fox, M. D. Dwyer, J. A. Landro, S. P.Chambers, W. Markland, C. A. Lepre, E. T. O'Malley, S. L. Harbeson, C.M. Rice, M. A. Murcko, P. R. Caron, J. A. Thomson, Cell, 1996, 87,343-55; R. A. Love, H. E. Parge, J. A. Wickersham, Z. Hostomsky, N.Habuka, E. W. Moomaw, T. Adachi, Z. Hostomska, Cell, 1996, 87, 331-342),herpes (W. Gibson, M. R. Hall, Drug. Des. Discov. 1997, 15, 39-47)], andinflammatory, immunological, respiratory (P. R. Bernstein, P. D.Edwards, J. C. Williams, Prog. Med. Chem. 1994, 31, 59-120; T. E. Hugh,Trends Biotechnol. 1996, 14, 409-12,), cardiovascular (M. T. Stubbs, W.A. Bode, Thromb. Res. 1993, 69, 1-58; H. Fukami et al, CurrentPharmaceutical Design 1998, 4, 439-453), and neurodegenerative defectsincluding Alzheimer's disease (R. Vassar, B. D. Bennett, S. Babu-Kahn,S. Kahn, E. A. Mendiaz, Science, 1999, 286, 735-41), angiogenesis(Kaatinen M et al, Atherosklerosis 1996, 123 1-2, 123-131) and multiplesclerosis (Ibrahim MZ et al, J. Neuroimmunol 1996, 70, 131-138.

As most proteases bind their substrates in extended or β-strandconformations, good inhibitors must thus be able to mimic such aconformation. β-Hairpin mimetics are thus ideally suited to lock peptidesequences in an extended conformation.

Among proteases, serine proteases constitute important therapeutictargets. Serine proteases are classified by their substrate specificity,particularly by the type of residue found at P1, as either trypsin-like(positively charged residues Lys/Arg preferred at P1), elastase-like(small hydrophobic residues Ala/Val at P1), or chymotrypsin-like (largehydrophobic residues Phe/Tyr/Leu at P1). Serine proteases for whichprotease-inhibitor X-ray crystal data is available on the PDB data base(PDB: www.rcsb.org/pdb) include trypsin, α-chymotrypsin, γ-chymotrypsin,human neutrophil elastase, thrombin, subtilisin, human cytomegalovirus,proteinase A, achromobacter, human cathepsin G, glutamic acid-specificprotease, carbopeptidase D, blood coagulation factorVIIa, porcine factor1XA, mesentericopeptidase, HCV protease, and thermitase. Other serineproteases which are of therapeutic interest include tryptase, complementconvertase, hepatitis C-NS3 protease. Inhibitors of thrombin (e.g. J. L.Metha, L. Y. Chen, W. W. Nichols, C. Mattsson, D. Gustaffson, T. G. P.Saldeen, J. Cardiovasc. Phannacol. 1998, 31, 345-51; C. Lila, P.Gloanec, L. Cadet, Y. Herve, J. Fournier, F. Leborgne, T. J. Verbeuren,G. DeNanteuil, Synth. Comm. 1998, 28, 4419-29) and factor Xa (e.g. J. P.Vacca, Annu. Rep. Med. Chem. 1998, 33, 81-90) are in clinical evaluationas anti-thrombotics, inhibitors of elastase (J. R. Williams, R. C.Falcone, C. Knee, R. L. Stein, A. M. Strimpler, B. Reaves, R. E. Giles,R. D. Krell, Am. Rev. Respir. Dis. 1991, 144, 875-83) are in clinicaltrials for emphysema and other pulmonary diseases whereas tryptaseinhibitors are currently in phase II clinical trials for asthma (C.Seife, Science 1997, 277, 1602-3), urokinase inhibitors for breastcancer, and chymase inhibitors for heart related diseases. Finally,cathepsin G and elastase are intimately involved in the modulation ofactivities of cytokines and their receptors. Particularly at sites ofinflammation, high concentration of cathepsin G, elastase and proteinase3 are released from infiltrating polymorphonuclear cells in closetemporal correlation to elevated levels of inflammatory cytokines,strongly indicating that these proteases are involved in the control ofcytokine bioactivity and availability (U. Bank, S. Ansorge, J. Leukoc.Biol. 2001, 69, 177-90). Thus inhibitors of elastase and cathepsin Gconstitute valuable targets for novel drug candidates particularly forchronic obstructive pulmonary disease (Ohbayashi H, Epert Opin.Investig. Drugs 2002, 11, 965-980).

Of the many occurring proteinaceous serine protease inhibitors, one is a14 amino acid cyclic peptide from sunflower seeds, termed sunflowertrypsin inhibitor (SFTI-1) (S. Luckett, R. Santiago Garcia, J. J.Barker, A. V. Konarev, P. R. Shewry, A. R. Clarke, R. L. Brady, J. Mol.Biol. 1999, 290, 525-533; Y.-Q. Long, S.-L. Lee, C.-Y. Lin, I. J.Enyedy, S. Wang, P. Li, R. B. Dickson, P. P. Roller, Biorg. & Med. Chem.Lett. 2001, 11, 2515-2519), which shows both sequence and conformationalsimilarity with the trypsin-reactive loop of the Bowman-Birk family ofserine protease inhibitors. The inhibitor adopts a β-hairpinconformation when bound to the active site of bovine β-trypsin. SFTI-1inhibited β-trypsin (K_(i)<0.1 nM), cathepsin G (K_(i)˜0.15 nM),elastase (K_(i)˜105 μM), chymotrypsin (K_(i)˜7.4 μM) and thrombin(K_(i)˜136 mM).

BRIEF SUMMARY OF THE INVENTION

We illustrate here an approach to inhibitor design which involvestransplanting the β-hairpin loop from the naturally occurring peptideonto a hairpin-inducing template. Based on the well defined 3D-structureof the β-hairpin mimetics, libraries of compounds can be designed whichultimately can lead to novel inhibitors showing different specificityprofiles towards several classes of proteases.

Template-bound hairpin mimetic peptides have been described in theliterature (D, Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem.1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441), and serineproteinase-inhibiting template-fixed peptidomimetics and methods fortheir synthesis have been described in International Patent ApplicationWO2003/054000 A1 and in Descours A, Moehle K., Renard A, Robinson J.ChemBioChem 2002, 3, 318-323 but the previously disclosed molecules donot exhibit high selectivity and particularly high potency. However, theability to generate β-hairpin peptidomimetics using combinatorial andparallel synthesis methods has now been established (L. Jiang, K.Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000,83, 3097-3112).

These methods allow the synthesis and screening of large hairpin mimeticlibraries, which in turn considerably facilitates structure-activitystudies, and hence the discovery of new molecules with highly potent andselective serine protease inhibitory activity, oral bioavailability, lowhemolytic activity to human red blood cells and low cytotoxicity.

DETAILED DESCRIPTION OF THE INVENTION

The β-hairpin peptidomimetics of the present invention are compounds ofthe general formula

wherein

is a group of one of the formulae

wherein

is Gly or the residue of an L-α-amino acid with B being a residue offormula —NR²⁰CH(R⁷¹)— or the enantiomer of one of the groups A1 to A69as defined hereinafter;

is a group of one of the formulae

-   R¹ is H; lower alkyl; or aryl-lower alkyl;-   R² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷ ; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NeR³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R^(8;)-   R⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁶ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³ R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; lower alkenyl; aryl;    aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵,    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶, —(CH₂)_(o)(CHR⁶¹)NR³³R³⁴ ;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R^(82; —(CH) ₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;-   R⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁰ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R¹² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)r(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)₁(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)₁(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹³ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s) C₆H₄R⁸;-   R¹⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁶ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(r)NR³³R³⁴;    —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(q)(CHR⁶¹),1)_(o)(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁸ is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)₅NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁹ is lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    (CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or-   R¹⁸ and R¹⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂0(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R²⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²³ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R^(82;) —(CH₂)_(o)(CHR⁶¹)_(r)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(r)PO(OR⁶)₂;    —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁶ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²,    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or-   R²⁵ and R²⁶ taken together can form: —(CH₂)₂₋₆—;    —(CH₂)_(r)O(CH₂)_(r)—; —(CH₂)_(r)S(CH₂)_(r)—; or    —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—;-   R²⁷ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R^(75; —(CH)    ₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁸ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)-OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s) SR⁵⁶, —(CH₂)_(o)(CHR⁶¹)_(s) NR³³ _(R) ³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s) COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s) CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s) PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R²⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R³¹ is H; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONfeR⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³² is H; lower alkyl; or aryl-lower alkyl;-   R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁴ is H; lower alkyl; aryl, or aryl-lower alkyl;-   R³³ and R³⁴ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R^(34; —(CH) ₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s) C₆H₄R⁸;-   R³⁶ is H, alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NeR³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁷ is H; F; Br; Cl; NO₂; CF₃; lower alkyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁸ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁹ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁴² is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁴³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R^(34; —(CH) ₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴⁴ is alkyl; alkenyl; —(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(s)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴⁶ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸;-   R⁴⁷ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;-   R⁴⁸ is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;-   R⁴⁹ is H; alkyl; alkenyl; —(CHR⁶¹)_(s)COOR⁵⁷;    (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CHR⁶¹)_(s)SOR⁶²; or    —(CHR⁶¹)_(s)C₆H₄R⁸;

R⁵⁰ is H; lower alkyl; or aryl-lower alkyl;

-   R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)2; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)2; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)2; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R^(34; —(CH) ₂)_(m)(CHR⁶¹)_(s)OCONR³³e;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵⁵ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONeR⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;-   R⁵⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;-   R⁵⁷ is H; lower alkyl; lower alkenyl; aryl lower alkyl; or    heteroaryl lower alkyl;-   R⁵⁸ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower    alkyl; or heteroaryl-lower alkyl;-   R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower    alkyl; or heteroaryl-lower alkyl; or-   R⁵⁸ and R⁵⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;-   R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;    heteroaryl-lower alkyl; —(CH₂)_(m)OR⁵⁵; —(CH₂)_(m)NR³³R³⁴;    —(CH₂)_(m)OCONR⁷⁸R⁸²; —(CH₂)_(o)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)COOR³⁷;    —(CH₂)_(o)NR⁵⁸R⁵⁹; or —(CH₂)_(o)PO(COR⁶⁰)₂;-   R⁶² is lower alkyl; lower alkenyl; aryl, heteroaryl; or aryl-lower    alkyl;-   R⁶³ is H; lower alkyl; lower alkenyl; aryl, heteroaryl; aryl-lower    alkyl; heteroaryl-lower alkyl; —COR⁶⁴; —COOR⁵⁷; —CONR⁵⁸R⁵⁹; —SO₂R⁶²;    or —PO(OR⁶⁰)2;-   R³⁴and R⁶³ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁶⁴ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower    alkyl; heteroaryl-lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³;    —(CH₂)p(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)p(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;-   R⁶⁵ is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;    heteroaryl-lower alkyl; —COR⁵⁷; —COOR⁵⁷; or —CONR⁵⁸R⁵⁹;-   R⁶⁶ is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;    heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹;-   m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1;

Z is a chain of 11 α-amino acid residues, the positions of said aminoacid residues in said chain being counted starting from the N-terminalamino acid, whereby these amino acid residues are, depending on theirposition in the chains, Gly, Pro, Pro(4NHCOPhe) or of formula -A-CO—, orof formula —B—CO—, or of one of the types

-   C: —NR²⁰CH(R⁷²)CO—;-   D: —NR²⁰CH(R⁷³)CO—;-   E: —NR²⁰CH(R⁷⁴)CO—;-   F: —NR²⁰CH(R⁸⁴)CO—; and-   H: —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;    —NR²⁰—CH(CO—)—(CH₂)_(p)S(CH₂)_(p)—CH(CO—)—NR²⁰—;    —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and    —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;-   R⁷¹ is lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR^(°)CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵;    —(CH₂)_(p)CONR⁵⁸R⁵⁹; —(CH₂)_(p)PO(OR⁶²)2; —(CH₂)_(p)SO₂R⁶²; or    —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;-   R⁷² is H, lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵; or    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵;-   R⁷³ is —(CR⁸⁶R⁸⁷)_(o)R⁷⁷; —(CH₂)_(r)O(CH₂)_(o)R⁷⁷;    —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or —(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷;-   R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;    —(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NOR⁷⁹; —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;    —(CH₂)_(r)O(CH₂),6NR⁷⁸R⁷⁹; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;    —(CH₂)_(r)O(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(i)0(CH₂),₆NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;—(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂),6N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰COR⁶⁴;    —(CH₂)_(p)NR⁸⁰COR⁷⁷; —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; or —(CH₂)_(p)NR²⁰CO—[(CH₂)_(o).-X]t—CH3    where X is -0—; —NR²⁰-, or -S-; u is 1-3, and t is 1-6;-   R⁷⁵ is lower alkyl; lower alkenyl; or aryl-lower alkyl;-   R³³ and R⁷⁵ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁷⁵ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CH₂)_(m)OR⁷²; —(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴;    —(CH₂)_(o)OCONR³³R⁷⁵; —(CH₂)_(o)NR²⁰CONR³³R⁸²; —(CH₂)_(o)COOR⁷⁵;    —(CH₂)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(o)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or    —(CH₂)_(o)COR⁶⁴;-   R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; or a heteroaryl group of one of the    formulae

-   R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl;-   R⁷⁸ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; or-   R⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—: —(CH₂)₂O(CH₂)₂—; or    —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁸⁰ is H; or lower alkyl;-   R⁸¹ is H; lower alkyl; or aryl-lower alkyl;-   R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;-   R³³ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁸³ is H; lower alkyl; aryl; or —NR⁷⁸R⁷⁹;-   R⁸⁴ is —(CH₂)_(m)(CHR⁶¹)_(s)OH; —(CR⁸⁶R⁸⁷)p0R⁸⁰; —(CR⁸⁶R⁸⁷)pCOOR⁸⁰;    —(CH₂)_(m)(CHR⁶¹)_(s)SH; —(CR⁸⁶R⁸⁷)pSR⁸⁰; —(CH₂)_(p)CONR⁷⁸R⁷⁹;    —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; —(CR⁸⁶R⁸⁷)_(o)PO(OR⁶⁰)2;    —(CR⁸⁶R⁸⁷)_(p)SO₂R⁶° ; —(CR⁸⁶R⁸⁷)_(p)SOR⁶⁰;    —(CH₂)_(m)(CHR⁶¹)_(s)OPO(OR⁶⁰)2,; or —(CH₂)_(m)(CHR⁶¹)_(s)OSO₂R⁶⁰;-   R⁸⁵ is lower alkyl; or lower alkenyl;-   R⁸⁶ is H; lower alkyl, where H is maybe substituted by halogen; or    halogen;-   R⁸⁷ is H; lower alkyl, where H is maybe substituted by halogen; or    halogen; with the proviso that in said chain of 11 α-amino acid    residues Z    -   if n is 11, the amino acid residues in positions 1 to 11 are:        -   P1: of type C or of type D or of type E or of type F;        -   P2: of type C or of Type D or of type E, or of type F;        -   P3: or of type C, of type F, or the residue is Gly;        -   P4: of type C, or of type D, or of type F, or of type E, or            the residue is Gly or Pro;        -   P5: of type E, or of type C, or of type F, or the residue is            Gly or Pro;        -   P6: of type D, or of type F, or of type E or of type C, or            the residue is Gly or Pro;        -   P7: of type C, or of type E, or of type F, or of formula            -A-CO—, or the residue is Gly or Pro;        -   P8: of type D, or of type C, or of type F, or of formula            -A-CO, or the residue is Gly or Pro or Pro(4NHCOPhe);        -   P9: of type C, or of type D, or of type E, or of type F;        -   P10: of type D, or of type C, or of type F, or of type E;            and        -   P11: of type C, or of type D, or of type E, or of type F; or        -   P2 and P10, taken together, can form a group of type H; and    -   with the further proviso that if the template is ^(D)Pro^(L)Pro,        the amino acid residues in positions P1 to P11 are other than        -   P1: Arg        -   P2: Cys, linked with Cys in position P10 by a disulfide            bridge        -   P3: Thr        -   P4: Lys        -   P5: Ser        -   P6: Ile        -   P7: Pro        -   P8: Pro        -   P9: Ile        -   P10: Cys, linked with Cys in position P2 by a disulfide            bridge; and        -   P11: Phe-   and pharmaceutically acceptable salts thereof.

In accordance with the present invention these β-hairpin peptidomimeticscan be prepared by a process which comprises

(a) coupling an appropriately functionalized solid support with anappropriately N-protected derivative of that amino acid which in thedesired end-product is in position 5, 6 or 7, any functional group whichmay be present in said N-protected amino acid derivative being likewiseappropriately protected;

(b) removing the N-protecting group from the product thus obtained;

(c) coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in the desired end-product is oneposition nearer the N-terminal amino acid residue, any functional groupwhich may be present in said N-protected amino acid derivative beinglikewise appropriately protected;

(d) removing the N-protecting group from the product thus obtained;

(e) repeating steps (c) and (d) until the N-terminal amino acid residuehas been introduced;

(f) coupling the product thus obtained with a compound of the generalformula

-   -   wherein

is as defined above and X is an N-protecting group or, alternatively, if

is to be group (a1) or (a2), above,

-   -   (fa) coupling the product obtained in step (e) with an        appropriately N-protected derivative of an amino acid of the        general formula

HOOC—B—H III or HOOC-A-H IV

-   -   wherein B and A are as defined above, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;    -   (fb) removing the N-protecting group from the product thus        obtained; and    -   (fc) coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid of the above general        formula IV and, respectively, III, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected; and, respectively, if

-   -   is to be group (a3), above,    -   (fa′) coupling the product obtained in step (e) with an        appropriately N-protected derivative of an amino acid of the        above general formula III, any functional group which may be        present in said N-protected amino acid derivative being likewise        appropriately protected;    -   (fb′) removing the N-protecting group from the product thus        obtained; and    -   (fc′) coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid of the above general        formula III, any functional group which may be present in said        N-protected amino acid derivative being likewise appropriately        protected;

(g) removing the N-protecting group from the product obtained in step(f) or (fc) or (fc′);

(h) coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in the desired end-product is inposition 11, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected;

(i) removing the N-protecting group from the product thus obtained;

(j) coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in the desired end-product is oneposition farther away from position 11, any functional group which maybe present in said N-protected amino acid derivative being likewiseappropriately protected;

(k) removing the N-protecting group from the product thus obtained;

(l) repeating steps (j) and (k) until all amino acid residues have beenintroduced;

(m) if desired, selectively deprotecting one or several protectedfunctional group(s) present in the molecule and appropriatelysubstituting the reactive group(s) thus liberated;

(n) if desired, forming an interstrand linkage between side-chains ofappropriate amino acid residues at positions 2 and 10;

(o) detaching the product thus obtained from the solid support;

(p) cyclizing the product cleaved from the solid support;

(q) removing any protecting groups present on functional groups of anymembers of the chain of amino acid residues and, if desired, anyprotecting group(s) which may in addition be present in the molecule;and

(r) if desired, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.

Alternatively, the peptidomimetics of the present invention can beprepared by

(a′) coupling an appropriately functionalized solid support with acompound of the general formula

wherein

is as defined above and X is an N-protecting group or, alternatively, if

is to be group (a1) or (a2), above,

-   -   (a′a) coupling said appropriately functionalized solid support        with an appropriately N-protected derivative of an amino acid of        the general formula

HOOC—B—H III or HOOC-A-H IV

-   -   wherein B and A are as defined above, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected;    -   (a′b) removing the N-protecting group from the product thus        obtained; and    -   (a′c) coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid of the above general        formula IV and, respectively, III, any functional group which        may be present in said N-protected amino acid derivative being        likewise appropriately protected; and, respectively, if

-   -   is to be group (a3), above,    -   (a′a′) coupling said appropriately functionalized solid support        with an appropriately N-protected derivative of an amino acid of        the above general formula III, any functional group which may be        present in said N-protected amino acid derivative being likewise        appropriately protected;    -   (a′b′) removing the N-protecting group from the product thus        obtained; and    -   (a′c′) coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid of the above general        formula III, any functional group which may be present in said        N-protected amino acid derivative being likewise appropriately        protected;

(b′) removing the N-protecting group from the product obtained in step(a′), (a′c) or (a′c′);

(c′) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is in position 11, any functional group which may be presentin said N-protected amino acid derivative being likewise appropriatelyprotected;

(d′) removing the N-protecting group from the product thus obtained;

(e′) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is one position farther away from position 11, anyfunctional group which may be present in said N-protected amino acidderivative being likewise appropriately protected;

(f′) removing the N-protecting group from the product thus obtained;

(g′) repeating steps (e′) and (f′) until all amino acid residues havebeen introduced;

(h′) if desired, selectively deprotecting one or several protectedfunctional group(s) present in the molecule and appropriatelysubstituting the reactive group(s) thus liberated;

(i′) if desired forming an interstrand linkage between side-chains ofappropriate amino acid residues at positions 2 and 10;

(j′) detaching the product thus obtained from the solid support;

(k′) cyclizing the product cleaved from the solid support;

(l′) removing any protecting groups present on functional groups of anymembers of the chain of amino acid residues and, if desired, anyprotecting group(s) which may in addition be present in the molecule;and

(m′) if desired, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.

The peptidomimetics of the present invention can also be enantiomers ofthe compounds of formula I. These enantiomers can be prepared by amodification of the above processes in which enantiomers of all chiralstarting materials are used.

As used in this description, the term “alkyl”, taken alone or incombinations, designates saturated, straight-chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atoms.Similarly, the term “alkenyl” designates straight chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atomsand containing at least one or, depending on the chain length, up tofour olefinic double bonds. The term “lower” designates radicals andcompounds having up to 6 carbon atoms. Thus, for example, the term“lower alkyl” designates saturated, straight-chain or branchedhydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and thelike. The term “aryl” designates aromatic carbocyclic hydrocarbonradicals containing one or two six-membered rings, such as phenyl ornaphthyl, which may be substituted by up to three substituents such asBr, Cl, F, CF₃, NO₂, lower alkyl or lower alkenyl. The term “heteroaryl”designates aromatic heterocyclic radicals containing one or two five-and/or six-membered rings, at least one of them containing up to threeheteroatoms selected from the group consisting of O, S and N and saidring(s) being optionally substituted; representative examples of suchoptionally substituted heteroaryl radicals are indicated hereinabove inconnection with the definition of R⁷⁷.

The structural element -A-CO— designates amino acid building blockswhich in combination with the structural element —B—CO— form templates(a1) and (a2). The structural element

—B—CO— forms in combination with another structural element —B—CO—template (a3)_(o)The template (a3) is less preferred in formula I.Templates (a) through (p) constitute building blocks which have anN-terminus and a C-terminus oriented in space in such a way that thedistance between those two groups may lie between 4.0-5.5A. The peptidechain Z is linked to the C-terminus and the N-terminus of the templates(a) through (p) via the corresponding N- and C-termini so that thetemplate and the chain form a cyclic structure such as that depicted informula I. In a case as here where the distance between the N- andC-termini of the template lies between 4.0-5.5A the template will inducethe H-bond network necessary for the formation of a β-hairpinconformation in the peptide chain Z. Thus template and peptide chainform a β-hairpin mimetic.

The β-hairpin conformation is highly relevant for the serine proteaseinhibitory activity of the β-hairpin mimetics of the present invention.The β-hairpin stabilizing conformational properties of the templates (a)through (p) play a key role not only for the selective inhibitoryactivity but also for the synthesis process defined hereinabove, asincorporation of the templates at the beginning or near the middle ofthe linear protected peptide precursors enhances cyclization yieldssignificantly.

Building blocks A1-A69 belong to a class of amino acids wherein theN-terminus is a secondary amine forming part of a ring. Among thegenetically encoded amino acids only proline falls into this class. Theconfiguration of building block A1 through A69 is (D), and they arecombined with a building block —B—CO— of (L)-configuration. Preferredcombinations for templates (a1) are-^(D)A1-CO—^(L)B—CO— to^(D)A69-CO—^(L)B—CO—. Thus, for example, ^(D)Pro-^(L)Pro constitutes theprototype of templates (a1). Less preferred, but possible arecombinations

-^(L)A1-CO-^(D)B—CO— to -^(L)A69-CO—^(D)B—CO— forming templates(a2)_(o)Thus, for example, ^(L)Pro-^(D)Pro constitutes the prototype oftemplate (a2).

It will be appreciated that building blocks -A1-CO— to -A69-CO— in whichA has (D)-configuration, are carrying a group R¹ at the a-position tothe N-terminus. The preferred values for R¹ are H and lower alkyl withthe most preferred values for R¹ being H and methyl. It will berecognized by those skilled in the art, that A1-A69 are shown in(D)-configuration which, for R¹ being H and methyl, corresponds to the(R)-configuration. Depending on the priority of other values for R¹according to the Cahn, Ingold and Prelog-rules, this configuration mayalso have to be expressed as (S).

In addition to R¹ building blocks -A1-CO— to -A69-CO— can carry anadditional substituent designated as R² to R¹⁷. This additionalsubstituent can be H, and if it is other than H, it is preferably asmall to medium-sized aliphatic or aromatic group. Examples of preferredvalues for R² to R¹⁷ are:

R²: H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); (CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); (CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;R⁵⁷: H; or lower alkyl); (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or loweralkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); (CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

R⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷:

H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl;or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;orlower alkoxy).

R⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: where H; or lower alkyl);(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: alkyl; alkenyl;aryl; and aryl-lower alkyl; heteroaryl-lower alkyl); —(CH₂)_(o)COOR⁵⁷(where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (whereR⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵:

lower alkyl; or R³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(q)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;orlower alkoxy).

R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (whereR⁵⁵: lower alkyl; or lower alkenyl); (CH₂)_(o)SR⁵⁶ (where R⁵⁶: loweralkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R₁₀: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

R¹¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

R¹²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R¹³: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(r)COO⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl;or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)i1)_(o)(OR⁶⁰)2 (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or

—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R¹⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R¹⁵: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);particularly favoured are NR²⁰COlower alkyl (R²⁰═H; or lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);

—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

R¹⁶: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; orlower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R¹⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(q)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)iSO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

Among the building blocks A1 to A69 the following are preferred: A5 withR² being H, A8, A22, A25, A38 with R² being H, A42, A47 and A50. Mostpreferred are building blocks of type A8′:

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl;[(CH₂)_(u)-X]_(t)—CH₃, wherein X is —O—, —NR²⁰or —S—, u is 1-3 and t is1-6; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especially thosewherein R⁶⁴ is n-hexyl (A8′-1); n-heptyl (A8′-2); 4-(phenyl)benzyl(A8′-3); diphenylmethyl (A8′-4); 3-amino-propyl (A8′-5); 5-amino-pentyl(A8′-6); methyl (A8′-7); ethyl (A8′-8); isopropyl (A8′-9); isobutyl(A8′-10); n-propyl (A8′-11); cyclohexyl (A8′-12); cyclohexylmethyl(A8′-13); n-butyl (A8′-14); phenyl (A8′-15); benzyl (A8′-16);(3-indolyl)methyl (A8′-17); 2-(3-indolyl)ethyl (A8′-18);(4-phenyl)phenyl (A8′-19); n-nonyl (A8′-20); CH₃—OCH₂CH₂—OCH₂— andCH₃—(OCH₂CH₂)₂—OCH₂—.

Building block A70 belongs to the class of open-chain α-substitutedα-amino acids, building blocks A71 and A72 to the corresponding 13-aminoacid analogues and building blocks A73-A104 to the cyclic analogues ofA70. Such amino acid derivatives have been shown to constrain smallpeptides in well defined reverse turn or U-shaped conformations (C. M.Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W. Kabsch, C Sander,Biopolymers 1983, 22, 2577)_(o)Such building blocks or templates areideally suited for the stabilization of β-hairpin conformations inpeptide loops (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel PeptideMimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv.Med Chem. 1999, Vol.4, 1-68; P. Balaram, “Non-standard amino acids inpeptide design and protein engineering”, Curr. Opin. Struct. Biol. 1992,2, 845-851; M. Crisma, G. Valle, C. Toniolo, S. Prasad, R. B. Rao, P.Balaram, “β-turn conformations in crystal structures of model peptidescontaining a,a-disubstituted amino acids”, Biopolymers 1995, 35, 1-9; V.J. Hruby, F. Al-Obeidi, W. Kazmierski, Biochem. J. 1990, 268, 249-262).

It has been shown that both enantiomers of building blocks -A70-CO— toA104-CO— in combination with a building block —B—CO— of L-configurationcan efficiently stabilize and induce β-hairpin conformations (D.Obrecht, M. Altorfer, J. A. Robinson, “Novel Peptide Mimetic BuildingBlocks and Strategies for Efficient Lead Finding”, Adv. Med Chem. 1999,Vol.4, 1-68; D. Obrecht, C. Spiegler, P. Schönholzer, K. Müller, H.Heimgartner, F. Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D.Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schönholzer, K. Müller,Tetrahedron 1995, 51, 10883-10900; D. Obrecht, C. Lehmann, C. Ruffieux,P. Schonholzer, K. Müller, Helv. Chim. Acta 1995, 78, 1567-1587; D.Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P.Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.Obrecht, H. Karajiannis, C. Lehmann, P. Schönholzer, C. Spiegler, Helv.Chim. Acta 1995, 78, 703-714).

Thus, for the purposes of the present invention templates (a1) can alsoconsist of -A70-CO— to A104—CO— where building block A70 to A104 is ofeither (D)- or (L)-configuration, in combination with a building block—B—CO— of (L)-configuration.

Preferred values for R²⁰ in A70 to A104 are H or lower alkyl with methylbeing most preferred. Preferred values for R¹⁸, R¹⁹ and R²¹ to R²⁹ inbuilding blocks A70 to A104 are the following:

-   -   R¹⁸: lower alkyl.    -   R¹⁹: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);—(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or—(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R²¹: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or (CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy).

R²²: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF; lower alkyl; lower alkenyl;or lower alkoxy).

R²³: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);particularly favoured are NR²⁰COlower alkyl (R²⁰═H; or lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);

—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy);

R²⁴: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);particularly favoured are NR²⁰COlower alkyl (R²⁰═H ; or lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);

—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy);

R²⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R²⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

Alternatively, R²⁵ and R²⁶ taken together can be —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl).

R²⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁸ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl;

lower alkenyl; or lower alkoxy).

R²⁸: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁸⁸ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁸ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

R²⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; _(or) —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); particularly favored are NR²⁰COlower-alkyl (R²⁰═H; orlower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl);

—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

The preferred value for R^(23,) R²⁴ _(and) R²⁹ is —NR²⁰—CO-lower alkylwhere R²⁰ is H or lower alkyl.

For templates (b) to (p), such as (b1) and (1), the preferred values forthe various symbols are the following:

R¹: H; or lower Alkyl;

R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (whereR⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: loweralkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;

—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R²⁰: H; or lower alkyl.

R³⁰: H, methyl.

R³¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); (—CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂),C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl;lower alkenyl; or lower alkoxy); most preferred is —CH₂CONR⁵⁸R⁵⁹ (R⁵⁸:H; or lower alkyl; R⁵⁹: lower alkyl; or lower alkenyl).

R³²: H, methyl.

R³³: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴: lower alkyl; or loweralkenyl; R⁶³: H; or lower alkyl; or R³⁴ and R⁶³ taken together form:—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl) ;(CH₂)_(m)OCONR⁷⁵R⁸²(where R⁷⁵: lower alkyl; or lower alkenyl; R⁸²: H; orlower alkyl; or R⁷⁵ and R⁸² taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl);

—(CH₂)_(o)NR²⁰CONR⁷⁸R⁸² (where R²⁰: H; or lower lower alkyl; R⁷⁸: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R⁷⁸ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl).

R³⁴: H; or lower alkyl.

R³⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl).

R³⁶: lower alkyl; lower alkenyl; or aryl-lower alkyl.

R³⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H; or loweralkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸² takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alky; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R³⁸: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁸ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R³⁹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or loweralkyl; R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷:lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: loweralkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).

R⁴⁰: lower alkyl; lower alkenyl; or aryl-lower alkyl.

R⁴¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;and R⁵⁹: H; lower alky; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R⁴²: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl);

—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R⁴³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy).

R⁴⁴: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵: lower alkyl;or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower alkyl; or loweralkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower alkyl; or lower alkenyl;R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R⁴⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R⁴⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(s)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(s)SR⁵⁶ (where R⁵⁶: lower alkyl; orlower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower alkyl; or loweralkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; orlower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(r)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(s)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R⁴⁷: H; or OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl).

R⁴⁸: H; or lower alkyl.

R⁴⁹: H;lower alkyl; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or (CH₂)_(s)C6H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

R⁵⁰: H; methyl.

R⁵¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); (CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); or —(CH₂),C₆H₄R⁸ (where R⁸: H; F; Cl;CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁵²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl;CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁵³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵: loweralkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower alkyl; orlower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken togetherform: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or

—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—;

—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl);

—(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³ and R⁸²taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);

—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl;or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or loweralkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:

—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H; or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl;CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

R⁵⁴: lower alkyl; lower alkenyl; or aryl-lower alkyl.

Most preferably R¹ is H; R^(°)is H; _(R) ³⁰ is H; R³¹ is carboxymethyl;or lower alkoxycarbonylmethyl; R³² is H; R³⁵ is methyl; R³⁶ is methoxy;R³⁷ is H and R³⁸ is H.

Among the building blocks A70 to A104 the following are preferred: A74with R²² being H, A75, A76, A77 with R²² being H, A78 and A79.

The building block —B—CO— within templates (a1), (a2) and (a3)designates an L-amino acid residue. Preferred values for B are:—NR²⁰CH(R⁷¹)- and enantiomers of groups A5 with R² being H, A8, A22,A25, A38 with R² being H, A42, A47, and A50. Most preferred are

Ala L-Alanine Arg L-Arginine Asn L-Asparagine Cys L-Cysteine GlnL-Glutamine Gly Glycine His L-Histidine Ile L-Isoleucine Leu L-LeucineLys L-Lysine Met L-Methionine Phe L-Phenylalanine Pro L-ProlinePro(5RPhe) (2S,5R)-5-phenylpyrrrolidine-2-carbocyclic acid Ser L-SerineThr L-Threonine Trp L-Tryptophan Tyr L-Tyrosine Val L-Valine CitL-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine t-BuGL-tert.-Butylglycine 4AmPhe L-para-Aminophenylalanine 3AmPheL-meta-Aminophenylalanine 2AmPhe L-ortho-AminophenylalaninePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂₋PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine TicL-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys L-N-Acetyllysine Dpr L-2,3-Diaminopropionic acid A₂BuL-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hChaL-Homo-cyclohexylalanine hCys L-Homo-cysteine hSer L-Homo-serine hArgL-Homo-arginine hPhe L-Homo-phenylalanine Bpa L-4-BenzoylphenylalaninePip L-Pipecolic acid OctG L-Octylglycine MePhe L-N-MethylphenylalanineMeNle L-N-Methylnorleucine MeAla L-N-Methylalanine MeIleL-N-Methylisoleucine MeVal L-N-Methvaline MeLeu L-N-Methylleucine

In addition, the most preferred values for B also include groups of typeA8″ of (L)-configuration:

-   -   wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl;        —[(CH₂)_(u)—X]_(t)—CH₃ (where X is    -   —O—; —NR²⁰—, or —S—, u is 1-3 and t is 1-6), aryl; aryl-lower        alkyl; or heteroaryl-lower alkyl; especially those wherein R⁶⁴        is n-hexyl (A8″-21); n-heptyl (A8″-22); n-(phenyl)benzyl        (A8″-23); diphenylmethyl (A8″-24); 3-amino-propyl (A8″-25);        5-amino-pentyl (A8″-26); methyl (A8″-27); ethyl (A8″-28);        isopropyl (A8″-29); isobutyl (A8″-30); n-propyl (A8″-31);        cyclohexyl (A8″-32); cyclohexylmethyl (A8″-33); n-butyl        (A8″-34); phenyl (A8″-35); benzyl (A8″-36); (3-indolyl)methyl        (A8″-37); 2-(3-indolyl)ethyl (A8″-38); (4-phenyl)phenyl        (A8″-39); n-nonyl (A8″-40); CH₃-OCH₂CH₂-OCH₂— (A8″-41) and        CH₃—(OCH₂CH₂)₂—OCH₂— (A8″-42).

The peptidic chain Z of the β-hairpin mimetics described herein isgenerally defined in terms of amino acid residues belonging to one ofthe following groups:

-   -   Group C —NR²⁰CH(R⁷²)CO—; “hydrophobic: small to medium-sized”    -   Group D —NR²⁰CH(R⁷³)CO—; “hydrophobic: large aromatic or        heteroaromatic”    -   Group E —NR²⁰CH(R⁷⁴)CO—; “polar-cationic” and “urea-derived”    -   Group F —NR²⁰CH(R⁸⁴)CO—; “polar-non-charged or anionic”    -   Group H —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;        “interstrand linkage”

Furthermore, the amino acid residues in chain Z can also be of formula-A-CO— or of formula —B—CO— wherein A and B are as defined above.Finally, Gly can also be an amino acid residue in chain Z, and Pro andPro(4-NHCOPhe) can be amino acid residues in chain Z, too, with theexception of positions where an interstrand linkage (H) is possible.

Group C comprises amino acid residues with small to medium-sizedhydrophobic side chain groups according to the general definition forsubstituent R⁷². A hydrophobic residue refers to an amino acid sidechain that is uncharged at physiological pH and that is repelled byaqueous solution. Furthermore these side chains generally do not containhydrogen bond donor groups, such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas. However, they may contain hydrogen bond acceptorgroups such as ethers, thioethers, esters, tertiary amides, alkyl- oraryl phosphonates and phosphates, or tertiary amines. Geneticallyencoded small-to-medium-sized amino acids include alanine, isoleucine,leucine, methionine and valine.

Group D comprises amino acid residues with aromatic and heteroaromaticside chain groups according to the general definition for substituentR⁷³. An aromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedπ-electron system (aromatic group). In addition they may containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas, and hydrogen bond acceptor groups such as (but notlimited to) ethers, thioethers, esters, tertiary amides, alkyl- or arylphosphonates and phosphates, or tertiary amines Genetically encodedaromatic amino acids include phenylalanine and tyrosine.

A heteroaromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedπ-system incorporating at least one heteroatom such as (but not limitedto) O, S and N according to the general definition for substituent R⁷⁷.In addition such residues may contain hydrogen bond donor groups such as(but not limited to) primary and secondary amides, primary and secondaryamines and the corresponding protonated salts thereof, thiols, alcohols,phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptorgroups such as (but not limited to) ethers, thioethers, esters, tertiaryamides, alkyl- or aryl phosphonates and phosphates, or tertiary aminesGenetically encoded heteroaromatic amino acids include tryptophan andhistidine.

Group E comprises amino acids containing side chains withpolar-cationic, acylamino- and urea-derived residues according to thegeneral definition for substituent R⁷⁴. Polar-cationic refers to a basicside chain which is protonated at physiological pH. Genetically encodedpolar-cationic amino acids include arginine, lysine and histidine.Citrulline is an example for an urea derived amino acid residue.

Group F comprises amino acids containing side chains withpolar-non-charged or anionic residues according to the generaldefinition for substituent R⁸⁴. A polar-non-charged or anionic residuerefers to a hydrophilic side chain that is uncharged and, respectivelyanionic at physiological pH (carboxylic acids being included), but thatis not repelled by aqueous solutions. Such side chains typically containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, carboxylic acids and esters, primary and secondaryamines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas.These groups can form hydrogen bond networks with water molecules. Inaddition they may also contain hydrogen bond acceptor groups such as(but not limited to) ethers, thioethers, esters, tertiary amides,carboxylic acids and carboxylates, alkyl- or aryl phosphonates andphosphates, or tertiary amines. Genetically encoded polar-non-chargedamino acids include asparagine, cysteine, glutamine, serine andthreonine, but also aspartic acid and glutamic acid.

Group H comprises side chains of preferably (L)-amino acids at oppositepositions of the β-strand region that can form an interstrand linkage.The most widely known linkage is the disulfide bridge formed bycysteines and homo-cysteines positioned at opposite positions of theβ-strand. Various methods are known to form disulfide linkages includingthose described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart etal., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company,III., 1984; Ahmed et al. J. Biol. Chem. 1975, 250, 8477-8482; andPennington et al., Peptides, pages 164-166, Giralt and Andreu, Eds.,ESCOM Leiden, The Netherlands, 1990. Most advantageously, for the scopeof the present invention, disulfide linkages can be prepared usingacetamidomethyl (Acm)-protective groups for cysteine. A well establishedinterstrand linkage consists in linking ornithines and lysines,respectively, with glutamic and aspartic acid residues located atopposite β-strand positions by means of an amide bond formation.Preferred protective groups for the side chain amino-groups of ornithineand lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic andglutamic acid. Finally, interstrand linkages can also be established bylinking the amino groups of lysine and ornithine located at oppositeβ-strand positions with reagents such as N,N-carbonylimidazole to formcyclic ureas.

As mentioned earlier, positions for an interstrand linkage are positionsP2 and 10, taken together. Such interstrand linkages are known tostabilize the β-hairpin conformations and thus constitute an importantstructural element for the design of β-hairpin mimetics.

Most preferred amino acid residues in chain Z are those derived fromnatural α-amino acids. Hereinafter follows a list of amino acids which,or the residues of which, are suitable for the purposes of the presentinvention, the abbreviations corresponding to generally adopted usualpractice:

three letter code one letter code Ala L-Alanine A Arg L-Arginine R AsnL-Asparagine N Asp L-Aspartic acid D Cys L-Cysteine C Glu L-Glutamicacid E Gln L-Glutamine Q Gly Glycine G His L-Histidine H IleL-Isoleucine I Leu L-Leucine L Lys L-Lysine K Met L-Methionine M PheL-Phenylalanine F Pro L-Proline P ^(D)Pro D-Proline ^(D)P Ser L-Serine SThr L-Threonine T Trp L-Tryptophan W Tyr L-Tyrosine Y Val L-Valine V

Other α-amino acids which, or the residues of which, are suitable forthe purposes of the present invention include:

Cit L-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine PenL-Penicillamine t-BuG L-tert.-Butylglycine 4AmPheL-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine 2AmPheL-ortho-Aminophenylalanine Phe(mC(NH₂)═NH) L-meta-AmidinophenylalaninePhe(pC(NH₂)═NH) L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine Tic1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys N-Acetyllysine Dpr 2,3-Diaminopropionic acid A₂Bu2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine BipL-(4-phenyl)phenylalanine S(Bzl) L-O-Benzylserine T(Bzl)L-O-Benzylthreonine hCha L-Homo-cyclohexylalanine hCys L-Homo-cysteinehSer L-Homo-serine hArg L-Homo-arginine hPhe L-Homo-phenylalanine BpaL-4-Benzoylphenylalanine 4-AmPyrr1(2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid 4-AmPyrr2(2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid 4-PhePyrr1(2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid 4-PhePyrr2(2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr1(2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr2(2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid Pro(4-OH)1(4S)-L-Hydroxyproline Pro(4-OH)2 (4R)-L-Hydroxyproline Pip L-Pipecolicacid ^(D)Pip D-Pipecolic acid OctG L-Octylglycine NGly N-MethylglycineMePhe L-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAlaL-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-MethylvalineMeLeu L-N-Methylleucine DimK L-(N′,N′Dimethyl)-lysine Lpzp L-Piperazinicacid Dpzp D-Piperazinic acid Isorn L-(N′,N′-diisobutyl)-ornithine PipAlaL-2-(4′-piperidinyl)-alanine PirrAla L-2-(3′-pyrrolidinyl)-alanine Ampc4-Amino-piperidine-4-carboxylic acid NMeR L-N-Methylarginine NMeKL-N-Methyllysine NMePhe L-N-Methylphenylalanine IPegKL-2-Amino-6-{2-[2-(2-methoxy- ethoxy)ethoxy]acetylamino}-hexanoic acidSPegK L-2-Amino-6-[2-(2methoxy-ethoxy)- acetylamino]-hexanoic acid DabL-2,4-Diamino-butyric acid IPegDab L-2-Amino-4{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetylamino}-butyric acid SPegDabL-2-Amino-4[2-(2-methoxy-ethoxy)- acetylamino] butyric acid 4-PyrAlaL-2-(4′Pyridyl)-alanine OrnPyr L-2-Amino-5-[(2′carbonylpyrazine)]amino-pentanoic acid BnG N-Benzylglycine AlloT Allo-Threonin Pro(4NHCOPhe)(2S)-4-benzamidino-pyrrolidine-2-carboxylic acid Aoc 2-(S)-Aminooctanoicacid

Particularly preferred residues for group C are:

Ala L-Alanine Ile L-Isoleucine Leu L-Leucine Met L-Methionine ValL-Valine tBuA L-t-Butylalanine t-BuG L-tert.-Butylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine hCha L-Homo-cyclohexylalanineOctG L-Octylglycine MePhe L-N-Methylphenylalanine MeNleL-N-Methylnorleucine MeAla L-N-Methylalanine MeIle L-N-MethylisoleucineMeVal L-N-Methylvaline MeLeu L-N-Methylleucine Aoc 2-(S)-Aminooctanoicacid

Particularly preferred residues for group D are:

His L-Histidine Phe L-Phenylalanine Trp L-Tryptophan Tyr L-Tyrosine PhgL-Phenylglycine 2-Nal L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine4Cl-Phe L-4-Chlorophenylalanine 3Cl-Phe L-3-Chlorophenylalanine 2Cl-PheL-2-Chlorophenylalanine 3,4Cl₂-Phe L-3,4-Dichlorophenylalanine 4F-PheL-4-Fluorophenylalanine 3F-Phe L-3-Fluorophenylalanine 2F-PheL-2-Fluorophenylalanine Thi L-β-2-Thienylalanine TzaL-2-Thiazolylalanine Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hPheL-Homo-phenylalanine Bpa L-4-Benzoylphenylalanine PirrAlaL-2-(3′-pyrrolidinyl)-alanine NMePhe L-N-Methylphenylalanine 4-PyrAlaL-2-(4′Pyridyl)-alanine

Particularly preferred residues for group E are

Arg L-Arginine Lys L-Lysine Orn L-Ornithine Dpr L-2,3-Diaminopropionicacid A₂Bu L-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acidPhe(pNH₂) L-para-Aminophenylalanine Phe(mNH₂) L-meta-AminophenylalaninePhe(oNH₂) L-ortho-Aminophenylalanine hArg L-Homo-argininePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine DimK L-(N′,N′Dimethyl)-lysine IsornL-(N′,N′-diisobutyl)-ornithine NMeR L-N-Methylarginine NMeKL-N-Methyllysine IPegK L-2-Amino-6-{2-[2-(2-methoxy-ethoxy)ethoxy]acetylamino}-hexanoic acid SPegKL-2-Amino-6-[2-(2methoxy-ethoxy)- acetylamino]-hexanoic acid DabL-2,4-Diamino-butyric acid IPegDab L-2-Amino-4{2-[2-(2-methoxy-ethoxy)-ethoxy]-acetylamino}-butyric acid SPegDabL-2-Amino-4[2-(2-methoxy-ethoxy)- acetylamino] butyric acid OrnPyrL-2-Amino-5-[(2′carbonylpyrazine)]amino- pentanoic PipAlaL-2-(4′-piperidinyl)-alanine

Particularly preferred residues for group F are

Asn L-Asparagine Asp L-Aspartic acid Cys L-Cysteine Gln L-Glutamine GluL-Glutamic acid Ser L-Serine Thr L-Threonine AlloThr Allo Threonine CitL-Citrulline Pen L-Penicillamine AcLys L-N^(ε)-Acetyllysine hCysL-Homo-cysteine hSer L-Homo-serine

Generally, the peptidic chain Z within the β-hairpin mimetics of theinvention comprises 11 amino acid residues. The positions P1 to P11 ofeach amino acid residue in the chain Z are unequivocally defined asfollows: P1 represents the first amino acid in the chain Z that iscoupled with its N-terminus to the C-terminus of the templates (b)-(p),or of group —B—CO— in template (a1), or of group -A-CO— in template(a2), or of the group —B—CO— forming the C-terminus of template (a3);and P11 represents the last amino acid in the chain Z that is coupledwith its C-terminus to the N-terminus of the templates (b)-(p), or ofgroup -A-CO— in template (a1), or of group —B—CO— in template (a2), orof the group —B—CO— forming the N-terminus of template (a3)_(o)Each ofthe positions P1 to P11 will preferably contain an amino acid residuebelonging to one of the above types C, D, E, F, H, or of formula -A-CO—or of formula —B—CO—, or being Gly, Pro or Pro(4NHCOPhe) as follows:

In general the α-amino acid residues in positions 1 to 11 of the chain Zare preferably:

-   -   P1: of type C, or of type D, or of type E, or of type F;    -   P2: of type E, or of type F, or of type C;    -   P3: or of type C, of type F or the residue is Gly;    -   P4: of type C, or of type E, or of type F, or the residue is Gly        or Pro;    -   P5: of type E, or of type F, or the residue is Gly or Pro;    -   P6: of type C, or of type D, or of type F, or the residue is Gly        or Pro;    -   P7: of type F or of formula -A-CO-or the residue is Gly or Pro;    -   P8: of type D, or of type C, or of formula -A-CO or the residue        is Gly or Pro or Pro(4NHCOPhe);    -   P9: of type C, or of type D, or of type E, or of type F;    -   P10: of type F, or of type C, or type E;    -   P11: of type E, or of type F, or of type C or of type D; or    -   P2 and P10, taken together, form a group of type H;

with the proviso that if template is ^(D)Pro-^(L)Pro the amino acidresidues in positions P1 to P11 are other than

-   -   P1: Arg    -   P2: Cys, linked with Cys in position P10 by a disulfide bridge    -   P3: Thr    -   P4 Lys    -   P5 Ser    -   P6 Ile    -   P7 Pro    -   P8 Pro    -   P9 Ile    -   P10 Cys, linked with Cys in position P2 by a disulfide bridge;        and    -   P11 Phe.

The α-amino acid residues in positions 1 to 11 are most preferably:

-   -   P1: Nle, Ile, Aoc, hLeu, Chg, OctG, hPhe, 4AmPhe, Cha, Phe, Tyr,        2Cl-Phe, Trp, 1-Nal, Leu, Cha, or Arg;    -   P2: Cys, Glu, Nle, Thr, or Gln ;    -   P3: Thr, Ala or Abu;    -   P4: Lys, Nle, Ala, Abu, or Thr;    -   P5: Ser, AlloThr, or Dpr;    -   P6: Ile, Csal, Leu, Nle, Aoc, OctG, Cha, hLeu, hPhe, Chg, t-BuA,        Glu, or Asp;    -   P7: Pro;    -   P8: Pro, Ala, or Pro(4NHCOPhe);    -   P9: Tyr, Phe, Ile, Nle, Cha, Gln, Arg, Lys, His, Thr, or Ala;    -   P10: Cys, Arg, Nle, Gln, Lys, Met, Thr, or Ser;    -   P11: Tyr, Gln, Arg, Ser, Nle, 2-Nal, 2Cl-Phe, Cha, Phg, Tyr,        Phe, Asp, Asn, or Thr; and    -   Cys, if present at P2 and P10, may form a disulfide bridge.

For inhibitors of Cathepsin G the α-amino acid residues in positions 1to 11 of the chain Z are preferably:

-   -   P1: of type C, or of type D, or of type E;    -   P2: of type F, or of type C;    -   P3: of type F;    -   P4: of type C, or of type E;    -   P5: of type E, or of type F;    -   P6: of type F;    -   P7: of type F, or of formula -A-CO—, or the residue is Gly or        Pro;    -   P8: of type C, or of formula -A-CO—, or the residue is Gly or        Pro or    -   Pro(4NHCOPhe);    -   P9: of type C, or of type D, or of type F;    -   P10: of type F, or of type C, or type E;    -   P11: of type E, or of type D, or of type F; or    -   P2 and P10, taken together, form a group of type H.

For inhibitors of Cathepsin G, the α-amino acid residues in positions 1to 11 are most preferably

-   -   P1: Phe, hPhe, 4AmPhe, Nle, Chg, Ile, Tyr, Arg, Trp, 2Cl-Phe,        Arg, 1-Nal, or Cha;    -   P2: Cys, Glu, or Nle;    -   P3: Thr;    -   P4: Lys, or Nle;    -   P5: Ser, AlloThr, or Dpr;    -   P6: Asp, or Glu;    -   P7: Pro;    -   P8: Pro;    -   P9: Ile, Nle, Cha, Gln, Tyr, or Ala;    -   P10: Cys, Arg, or Nle;    -   P11: Thr, Asp, Ser, Tyr, Phe, Asn, or Arg; and    -   Cys, if present at P2 and P10, may form a disulfide bridge.

For inhibitors of Elastase the α-amino acid residues in positions 1 to11 of the chain Z are preferably

-   -   P1: of type C, or of type D;    -   P2: of type F;    -   P3: of type For of type C;    -   P4: of type C or of type F;    -   P5: of type F;    -   P6: of type C;    -   P7: of formula -A-CO-or the residue is Gly or Pro;    -   P8: of formula -A-CO or the residue is Gly or Pro or        Pro(4NHCOPhe);    -   P9: of type D, or of type F or of type C;    -   P10: of type F, or of type C, or type E;    -   P11: of type E, or of type F, or of type D; or    -   P2 and P10, taken together, form a group of type H.

For inhibitors of Elastase, the α-amino acid residues in positions 1 to11 are most preferably:

-   -   P1: Ile, Nle, Aoc, hLeu, Chg, OctG, or hPhe;    -   P2: Cys, Glu, Thr, or Gln;    -   P3: Thr, Ala, or Abu;    -   P4: Ala, Thr, or Abu;    -   P5: Ser;    -   P6: OctG, Ile, Cha, Leu, C₅al, Nle, Aoc, Chg, tBuA, or hLeu;    -   P7: Pro;    -   P8: Pro, or Pro(4NHCOPhe);    -   P9: Gln, Tyr, ILe, or Phe;    -   P10: Cys, Lys, Gln, Thr, Met, or Arg;    -   P11: Tyr, Ser, Arg, Gln, Nle, 2-Nal, 2Cl-Phe, Phe, Cha, or Phg;        and    -   Cys, if present at P2 and P10, may form a disulfide bridge.

For inhibitors of Tryptase the α-amino acid residues in positions 1 to11 of the chain Z are preferably:

-   -   P1: of type C, or of type D, or of type E;    -   P2: of type F;    -   P3: of type F;    -   P4: of type E;    -   P5: of type F;    -   P6: of type C, or of type D;    -   P7: of type F, or of formula -A-CO—, or the residue is Gly or        Pro;    -   P8: of type C, or of formula -A-CO—, or the residue is Gly or        Pro;    -   P9: of type C, or of type E, or of type F;    -   P10: of type F;    -   P11: of type E, or of type D; or    -   P2 and P10, taken together, form a group of type H; with the        proviso that if the template is ^(D)Pro-^(L)Pro, the amino acid        residues in positions P1 to P11 are other than    -   P1: Arg    -   P2: Cys, linked with Cys in position P10 by a disulfide bridge    -   P3: Thr    -   P4 Lys    -   P5 Ser    -   P6 Ile    -   P7 Pro    -   P8 Pro    -   P9 Ile    -   P10 Cys, linked with Cys in position P10 by a disulfide bridge;        and P11 Phe.

For inhibitors of Tryptase the α-amino acid residues in positions 1 to11 of the chain Z are most preferably:

-   -   P1: Cha, Tyr, or Trp    -   P2: Cys    -   P3: Thr    -   P4: Lys    -   P5: Ser    -   P6: Leu    -   P7: Pro    -   P8: Pro    -   P9: Lys    -   P10: Cys    -   P11: Arg; and

the Cys residues present at P2 and P10 may form a disulfide bridge.

Particularly preferred β-peptidomimetics of the invention include thosedescribed in Examples 5, 19, 20, 22, 23, 38, 39, 40, and 75 asinhibitors of cathepsin G; Examples 91, 121, 153, 154, 155, 156, 157,158, 159, 160, 161 177, and 178 as inhibitors of elastase; and Examples193, 194, and 195 as inhibitors of Tryptase.

The processes of the invention can advantageously be carried out asparallel array syntheses to yield libraries of template-fixed β-hairpinpeptidomimetics of the above general formula I. Such parallel synthesesallow one to obtain arrays of numerous (normally 24 to 192, typically96) compounds of general formula I in high yields and defined purities,minimizing the formation of dimeric and polymeric by-products. Theproper choice of the functionalized solid-support (i.e. solid supportplus linker molecule), templates and site of cyclization play therebykey roles.

The functionalized solid support is conveniently derived frompolystyrene crosslinked with, preferably 1-5%, divinylbenzene;polystyrene coated with polyethyleneglycol spacers (Tentagel^(R)); andpolyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M,“Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries”, Tetrahedron OrganicChemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. abifunctional spacer molecule which contains on one end an anchoringgroup for attachment to the solid support and on the other end aselectively cleavable functional group used for the subsequent chemicaltransformations and cleavage procedures. For the purposes of the presentinvention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acidicconditions (Rink H, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers ofthis kind form amides of the carboxyl group of the amino acids; examplesof resins functionalized by such linker structures include4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl] PS resin,4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl] -4-methylbenzydrylamine PS resin (Rink amide MBHA PSResin), and 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl]phenoxyacetamido)aminomethyl)benzhydrylamine PS-resin (Rink amide BHA PS resin).Preferably, the support is derived from polystyrene crosslinked with,most preferably 1-5%, divinylbenzene and functionalized by means of the4-(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) linker

Type 2 linkers are designed to eventually release the carboxyl groupunder acidic conditions. Linkers of this kind form acid-labile esterswith the carboxyl group of the amino acids, usually acid-labile benzyl,benzhydryl and trityl esters; examples of such linker structures include2-methoxy-4-hydroxymethylphenoxy (Sasrin^(R) linker),4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityland 2-chlorotrityl. Preferably, the support is derived from polystyrenecrosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 2-chlorotrityl linker.

When carried out as parallel array syntheses the processes of theinvention can be advantageously carried out as described herein belowbut it will be immediately apparent to those skilled in the art howthese procedures will have to be modified in case it is desired tosynthesize one single compound of the above formula I.

A number of reaction vessels (normally 24 to 192, typically 96) equal tothe total number of compounds to be synthesized by the parallel methodare loaded with 25 to 1000 mg, preferably 100 mg, of the appropriatefunctionalized solid support which is preferably derived frompolystyrene cross-linked with 1 to 3% of divinylbenzene, or fromTentagel resin.

The solvent to be used must be capable of swelling the resin andincludes, but is not limited to, dichloromethane (DCM),dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene,tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE),isopropylalcohol and the like. Solvent mixtures containing as at leastone component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) arebeneficial for ensuring high reactivity and solvation of the resin-boundpeptide chains (Fields, G. B., Fields, C. G., J. Am. Chem. Soc. 1991,113, 4202-4207).

With the development of various linkers that release the C-terminalcarboxylic acid group under mild acidic conditions, not affectingacid-labile groups protecting functional groups in the side chain(s),considerable progresses have been made in the synthesis of protectedpeptide fragments. The 2-methoxy-4-hydroxybenzylalcohol-derived linker(Sasrin^(R) linker, Mergler et al., Tetrahedron Lett. 1988, 294005-4008) is cleavable with diluted trifluoroacetic acid (0.5-1% TFA inDCM) and is stable to Fmoc deprotection conditions during the peptidesynthesis, Boc/tBu-based additional protecting groups being compatiblewith this protection scheme. Other linkers which are suitable for theprocesses of the invention include the super acid labile4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, Rink,H Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of thepeptide requires 10% acetic acid in DCM or 0.2% trifluoroacetic acid inDCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid-derived linker(HMPB-linker, Florsheimer & Riniker, Peptides 1991,1990 131) which isalso cleaved with 1%TFA/DCM in order to yield a peptide fragmentcontaining all acid labile side-chain protective groups; and, inaddition, the 2-chlorotritylchloride linker (Barbs et al., TetrahedronLett. 1989, 30, 3943-3946), which allows the peptide detachment using amixture of glacial acetic acid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino acids and, respectively, for theirresidues are, for example,

-   -   for the amino group (as is present e.g. also in the side-chain        of lysine)

Cbz benzyloxycarbonyl Boc tert.-butyloxycarbonyl Fmoc9-fluorenylmethoxycarbonyl Alloc allyloxycarbonyl Teoctrimethylsilylethoxycarbonyl Tcc trichloroethoxycarbonyl Npso-nitrophenylsulfonyl; Trt triphenymethyl or trityl

-   -   for the carboxyl group (as is present e.g. also in the        side-chain of aspartic and glutamic acid) by conversion into        esters with the alcohol components

tBu tert.-butyl Bn benzyl Me methyl Ph phenyl Pac Phenacyl Allyl Tsetrimethylsilylethyl Tce trichloroethyl;

-   -   for the guanidino group (as is present e.g. in the side-chain of        arginine)

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Ts tosyl (i.e.p-toluenesulfonyl) Cbz benzyloxycarbonyl Pbfpentamethyldihydrobenzofuran-5-sulfonyl

-   -   for the hydroxy group (as is present e.g. in the side-chain of        threonine and serine)

tBu tert.-butyl Bn benzyl Trt trityl

-   -   and for the mercapto group (as is present e.g. in the side-chain        of cysteine)

Acm acetamidomethyl tBu tert.-butyl Bn benzyl Trt trityl Mtr4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivativesare preferably used as the building blocks for the construction of thetemplate-fixed β-hairpin loop mimetics of formula I. For thedeprotection, i.e. cleaving off of the Fmoc group, 20% piperidine in DMFor 2% DBU/2% piperidine in DMF can be used.

The quantity of the reactant, i.e. of the amino acid derivative, isusually 1 to 20 equivalents based on the milliequivalents per gram(meq/g) loading of the functionalized solid support (typically 0.1 to2.85 meq/g for polystyrene resins) originally weighed into the reactiontube. Additional equivalents of reactants can be used, if required, todrive the reaction to completion in a reasonable time. The reactiontubes, in combination with the holder block and the manifold, arereinserted into the reservoir block and the apparatus is fastenedtogether. Gas flow through the manifold is initiated to provide acontrolled environment, for example, nitrogen, argon, air and the like.The gas flow may also be heated or chilled prior to flow through themanifold. Heating or cooling of the reaction wells is achieved byheating the reaction block or cooling externally with isopropanol/dryice and the like to bring about the desired synthetic reactions.Agitation is achieved by shaking or magnetic stirring (within thereaction tube). The preferred workstations (without, however, beinglimited thereto) are Labsource's Combi-chem station and MultiSynTech's-Syro synthesizer.

Amide bond formation requires the activation of the a-carboxyl group forthe acylation step. When this activation is being carried out by meansof the commonly used carbodiimides such as dicyclohexylcarbodiimide(DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) ordiisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res.Commun. 1976, 73, 336-342), the resulting dicyclohexylurea anddiisopropylurea is insoluble and, respectively, soluble in the solventsgenerally used. In a variation of the carbodiimide method1-hydroxybenzotriazole (HOBt, König & Geiger, Chem. Ber 1970, 103,788-798) is included as an additive to the coupling mixture. HOBtprevents dehydration, suppresses racemization of the activated aminoacids and acts as a catalyst to improve the sluggish coupling reactions.Certain phosphonium reagents have been used as direct coupling reagents,such as benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14,1219-1222; Synthesis, 1976, 751-752), orbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate(Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or2-(1H-benzotriazol-1-yl-)1,1,3,3-tetramethyluronium terafluoroborate(TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett.1989, 30, 1927-1930); these phosphonium reagents are also suitable forin situ formation of HOBt esters with the protected amino acidderivatives. More recently diphenoxyphosphoryl azide (DPPA) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpinoet al., Tetrahedron Lett. 1994, 35, 2279-2281) have also been used ascoupling reagents.

Due to the fact that near-quantitative coupling reactions are essential,it is desirable to have experimental evidence for completion of thereactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970,34, 595), where a positive colorimetric response to an aliquot ofresin-bound peptide indicates qualitatively the presence of the primaryamine, can easily and quickly be performed after each coupling step.Fmoc chemistry allows the spectrophotometric detection of the Fmocchromophore when it is released with the base (Meienhofer et al., Int.J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction tube is washed free ofexcess of retained reagents, of solvents, and of by-products byrepetitive exposure to pure solvent(s) by one of the two followingmethods:

1) The reaction wells are filled with solvent (preferably 5 ml), thereaction tubes, in combination with the holder block and manifold, areimmersed and agitated for 5 to 300 minutes, preferably 15 minutes, anddrained by gravity followed by gas pressure applied through the manifoldinlet (while closing the outlet) to expel the solvent;

2) The manifold is removed from the holder block, aliquots of solvent(preferably 5 ml) are dispensed through the top of the reaction tubesand drained by gravity through a filter into a receiving vessel such asa test tube or vial.

Both of the above washing procedures are repeated up to about 50 times(preferably about 10 times), monitoring the efficiency of reagent,solvent, and by-product removal by methods such as TLC, GC, orinspection of the washings.

The above described procedure of reacting the resin-bound compound withreagents within the reaction wells followed by removal of excessreagents, by-products, and solvents is repeated with each successivetransformation until the final resin-bound fully protected linearpeptide has been obtained.

Before this fully protected linear peptide is detached from the solidsupport, it is possible, if desired, to selectively deprotect one orseveral protected functional group(s) present in the molecule and toappropriately substitute the reactive group(s) thus liberated. To thiseffect, the functional group(s) in question must initially be protectedby a protecting group which can be selectively removed without affectingthe remaining protecting groups present. Alloc (allyloxycarbonyl) is anexample for such an amino protecting group which can be selectivelyremoved, e.g. by means of Pd° and phenylsilane in CH₂Cl₂, withoutaffecting the remaining protecting groups, such as Fmoc, present in themolecule. The reactive group thus liberated can then be treated with anagent suitable for introducing the desired substituent. Thus, forexample, an amino group can be acylated by means of an acylating agentcorresponding to the acyl substituent to be introduced. For theformation of pegylated amino acids such as IPegK, or SPegK, preferably asolution of 5 equivalents of HATU(N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide) in dry DMF and a solution of 10 equivalentsof DIPEA (Diisopropyl ethylamine) in dry DMF and 5 equivalents of2-[2-(2-methoxyethoxy)ethoxy] acetic acid (1Peg) and, respectively,2-(2-methoxyethoxy)acetic acid (sPeg), is applied to the liberated aminogroup of the appropriate amino acid side chain for 3 h. The procedure isthereafter repeated for another 3 h with a fresh solution of reagentsafter filtering and washing the resin.

Before this fully protected linear peptide is detached from the solidsupport, it is also possible, if desired, to form an interstrandlinkages between side-chains of appropriate amino acid residues atpositions 2 and 10.

Interstrand linkages and their formation have been discussed above, inconnection with the explanations made regarding groups of the type Hwhich can, for example, be disulfide bridges formed by cysteine andhomocysteine residues at opposite positions of the β-strand; or lactambridges formed by glutamic and aspartic acid residues linking ornithineand, respectively, lysine residues, or by glutamic acid residues linking2,4-diaminobutyric acid residues located at opposite β-strand positionsby amide bond formation. The formation of such interstrand linkages canbe effected by methods well known in the art.

For the formation of disulfide bridges preferably a solution of 10equivalents of iodine solution is applied in DMF or in a mixture ofCH₂Cl₂/MeOH for 1.5 h which is repeated for another 3 h with a freshiodine solution after filtering of the iodine solution, or in a mixtureof DMSO and acetic acid solution, buffered with 5% with NaHCO₃ to pH 5-6for 4h, or in water adjusted to pH 8 with ammonium hydroxide solution bystirring for 24h, or in ammonium acetate buffer adjusted to pH 8 in thepresence of air, or in a solution of NMP and tri-n-butylphosphine(preferably 50 eq.).

Detachment of the fully protected linear peptide from the solid supportis achieved by immersion of the reaction tubes, in combination with theholder block and manifold, in reaction wells containing a solution ofthe cleavage reagent (preferably 3 to 5 ml). Gas flow, temperaturecontrol, agitation, and reaction monitoring are implemented as describedabove and as desired to effect the detachment reaction. The reactiontubes, in combination with the holder block and manifold, aredisassembled from the reservoir block and raised above the solutionlevel but below the upper lip of the reaction wells, and gas pressure isapplied through the manifold inlet (while closing the outlet) toefficiently expel the final product solution into the reservoir wells.The resin remaining in the reaction tubes is then washed 2 to 5 times asabove with 3 to 5 ml of an appropriate solvent to extract (wash out) asmuch of the detached product as possible. The product solutions thusobtained are combined, taking care to avoid cross-mixing. The individualsolutions/extracts are then manipulated as needed to isolate the finalcompounds. Typical manipulations include, but are not limited to,evaporation, concentration, liquid/liquid extraction, acidification,basification, neutralization or additional reactions in solution.

The solutions containing fully protected linear peptide derivativeswhich have been cleaved off from the solid support and neutralized witha base, are evaporated. Cyclization is then effected in solution usingsolvents such as DCM, DMF, dioxane, THF and the like. Various couplingreagents which were mentioned earlier can be used for the cyclization.The duration of the cyclization is about 6-48 hours, preferably about 16hours. The progress of the reaction is followed, e.g. by RP-HPLC(Reverse Phase High Performance Liquid Chromatography). Then the solventis removed by evaporation, the fully protected cyclic peptide derivativeis dissolved in a solvent which is not miscible with water, such as DCM,and the solution is extracted with water or a mixture of water-misciblesolvents, in order to remove any excess of the coupling reagent.

Finally, the fully protected peptide derivative is treated with 95% TFA,2.5% H₂O, 2.5% TIS or another combination of scavengers for effectingthe cleavage of protecting groups. The cleavage reaction time iscommonly 30 minutes to 12 hours, preferably about 2.5 hours. Thevolatiles are evaporated to dryness and the crude peptide is dissolvedin 20% AcOH in water and extracted with isopropyl ether or othersolvents which are suitable therefor. The aqueous layer is collected andevaporated to dryness, and the fully deprotected cyclic peptidederivative of formula I is obtained as end-product.

Alternatively the detachment, cyclization and complete deprotection ofthe fully protected peptide from the solid support can be achievedmanually in glass vessels.

Depending on its purity, this peptide derivative can be used directlyfor biological assays, or it has to be further purified, for example bypreparative HPLC.

As mentioned earlier, it is thereafter possible, if desired, to converta fully deprotected product of formula I thus obtained into apharmaceutically acceptable salt or to convert a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt. Any of these operations can be carried out by methodswell known in the art.

The template starting materials of formula II used in the processes ofthe invention, pre-starting materials therefor, and the preparation ofthese starting and pre-starting materials are described in InternationalApplication PCT/EP02/01711 of the same applicants, published as WO02/070547 A1.

The β-hairpin peptidomimetics of the invention can be used in a widerange of applications where inflammatory diseases or pulmonary diseasesor infections or immunological diseases or cardiovascular diseases orneurodegenerative diseases are mediated or resulting from serineprotease activity, or where cancer is mediated or resulting from serineprotease activity. For the control or prevention of a given illness ordisease amenable to treatment with protease inhibitors, the β-hairpinpeptidomimetics may be administered per se or may be applied as anappropriate formulation together with carriers, diluents or excipientswell known in the art.

When used to treat or prevent diseases such as pulmonary emphysema,rheumatoid arthritis, osteoarthritis, atherosclerosis, psoriasis, cysticfibrosis, multiple sclerosis, adult respiratory distress syndrome,pancreatitis, asthma, allergic rhinitis, inflammatory dermatoses, postangioplasty restenosis, cardiac hypertrophy, heart failure or cancersuch as, but not limited to, breast cancer, or cancer related toangiogenesis or metastasis, the β-hairpin peptidomimetics can beadministered singly, as mixtures of several β-hairpin peptidomimetics,in combination with other anti-inflammatory agents, or antimicrobialagents or anti-cancer agents and/or in combination with otherpharmaceutically active agents. The β-hairpin peptidomimetics can beadministered per se or as pharmaceutical compositions.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, coated tablet-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxilliaries which facilitate processing of the active β-hairpinpeptidomimetics into preparations which can be used pharmaceutically.Proper formulation depends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of theinvention may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g. subcutaneous, intravenous, intramuscular, intrathecal orintraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may beformulated in adequate solutions, preferably in physiologicallycompatible buffers such as Hink's solution, Ringer's solution, orphysiological saline buffer. The solutions may contain formulatoryagents such as suspending, stabilizing and/or dispersing agents.Alternatively, the β-hairpin peptidomimetics of the invention may be inpowder form for combination with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation as known in the art.

For oral administration, the β-hairpin peptidomimetics of the inventioncan be readily formulated by combining them with pharmaceuticallyacceptable carriers well known in the art. Such carriers enable theβ-hairpin peptidomimetics of the invention to be formulated as tablets,pills, dragees, capsules, liquids, gels, syrups, slurries, suspensionsetc., for oral ingestion by a patient to be treated. For oralformulations such as, for example, powders, capsules and tablets,suitable excipients include fillers such as sugars, e.g. lactose,sucrose, mannitol and sorbitol; cellulose preparations such as maizestarch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulatingagents; and binding agents. If desired, disintegrating agents may beadded, such as cross-linked polyvinylpyrrolidones, agar, or alginic acidor a salt thereof, such as sodium alginate. If desired, solid dosageforms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,glycols, oils, alcohols, etc. In addition, flavoring agents,preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets,lozenges, etc., formulated as usual.

For administration by inhalation, the β-hairpin peptidomimetics of theinvention are conveniently delivered in form of an aerosol spray frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide oranother suitable gas. In the case of a pressurized aerosol the dose unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the β-hairpinpeptidomimetics of the invention and a suitable powder base such aslactose or starch.

The compounds may also be formulated in rectal or vaginal compositionssuch as suppositories together with appropriate suppository bases suchas cocoa butter or other glycerides.

In addition to the formulations described previously, the β-hairpinpeptidomimetics of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (e.g. subcutaneously or intramuscularly) or byintramuscular injection. For the manufacture of such depot preparationsthe β-hairpin peptidomimetics of the invention may be formulated withsuitable polymeric or hydrophobic materials (e.g. as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed suchas liposomes and emulsions well known in the art. Certain organicsolvents such as dimethylsulfoxide may also be employed. Additionally,the β-hairpin peptidomimetics of the invention may be delivered using asustained-release system, such as semipermeable matrices of solidpolymers containing the therapeutic agent. Various sustained-releasematerials have been established and are well known by those skilled inthe art. Sustained-release capsules may, depending on their chemicalnature, release the compounds for a few weeks up to over 100 days.Depending on the chemical nature and the biological stability of thetherapeutic agent, additional strategies for protein stabilization maybe employed.

As the β-hairpin pepdidomimetics of the invention may contain chargedresidues, they may be included in any of the above-describedformulations as such or as pharmaceutically acceptable salts.Pharmaceutically acceptable salts tend to be more soluble in aqueous andother protic solvents than are the corresponding free forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof,will generally be used in an amount effective to achieve the intendedpurpose. It is to be understood that the amount used will depend on aparticular application.

For topical administration to treat or prevent diseases amenable totreatment with beta hairpin mimetics a therapeutically effective dosecan be determined using, for example, the in vitro assays provided inthe examples. The treatment may be applied while the disease is visible,or even when it is not visible. An ordinary skilled expert will be ableto determine therapeutically effective amounts to treat topical diseaseswithout undue experimentation.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating β-hairpinpeptidomimetic concentration range that includes the IC₅₀ as determinedin the cell culture. Such information can be used to more accuratelydetermine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animalmodels, using techniques that are well known in the art. One havingordinary skill in the art could readily optimize administration tohumans based on animal data.

Dosage amounts for applications as serine protease inhibitory agents maybe adjusted individually to provide plasma levels of the β-hairpinpeptidomimetics of the invention which are sufficient to maintain thetherapeutic effect. Therapeutically effective serum levels may beachieved by administering multiple doses each day.

In cases of local administration or selective uptake, the effectivelocal concentration of the β-hairpin peptidomimetics of the inventionmay not be related to plasma concentration. One having the ordinaryskill in the art will be able to optimize therapeutically effectivelocal dosages without undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and thejudgment of the prescribing physician.

Normally, a therapeutically effective dose of the β-hairpinpeptidomimetics described herein will provide therapeutic benefitwithout causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the LD₅₀ (the dose lethal to50% of the population) or the Lthoo (the dose lethal to 100% of thepopulation). The dose ratio between toxic and therapeutic effect is thetherapeutic index. Compounds which exhibit high therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in humans. The dosage of the β-hairpin peptidomimetics of theinvention lies preferably within a range of circulating concentrationsthat include the effective dose with little or no toxicity. The dosagemay vary within the range depending upon the dosage form employed andthe route of administration utilized. The exact formulation, route ofadministration and dose can be chosen by the individual physician inview of the patient's condition (see, e.g. Fingl et al. 1975, In : ThePharmacological Basis of Therapeutics, Ch.1, p.1).

The following Examples illustrate the invention in more detail but arenot intended to limit its scope in any way. The following abbreviationsare used in these Examples:

-   -   HBTU: 1-benzotriazol-1-yl-tetramethylurounium        hexafluorophosphate (Knorr et al. Tetrahedron Lett. 1989, 30,        1927-1930);    -   HOBt: 1-hydroxybenzotriazole;    -   DIEA: diisopropylethylamine;    -   HOAT: 7-aza-1-hydroxybenzotriazole;    -   HATU: O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoium        hexafluorophosphate (Carpino et al. Tetrahedron Lett. 1994, 35,

EXAMPLES 1. Peptide Synthesis Coupling of the First Protected Amino AcidResidue to the Resin

0.5 g of 2-chlorotritylchloride resin (Barbs et al. Tetrahedron Lett.1989, 30, 3943-3946) (0.83 mMol/g, 0.415 mmol) was filled into a driedflask. The resin was suspended in CH₂Cl₂ (2.5 ml) and allowed to swellat room temperature under constant stirring for 30 min. The resin wastreated with 0.415 mMol (1 eq) of the first suitably protected aminoacid residue (see below) and 284 μl (4eq) of diisopropylethylamine(DIEA) in CH₂Cl₂ (2.5 ml), the mixture was shaken at 25° C. for 4 hours.The resin colour changed to purple and the solution remained yellowish.The resin was shaken (CH₂Cl₂/MeOH/DIEA: 17/2/1), 30 ml for 30 min; thenwashed in the following order with CH₂Cl₂(1×), DMF (1×), CH₂Cl₂ (1×),MeOH (1×), CH₂Cl₂ (1×), MeOH (1×), CH₂Cl₂ (2×), Et₂O (2×) and driedunder vacuum for 6 hours.

Loading was typically 0.6-0.7 mMol/g.

The following preloaded resins were prepared:Fmoc-Pro-2-chlorotritylresin, Fmoc-Asp (OtBu)-2-chlorotritylresin,Fmoc-Pro(5RPhe)-2-chlorotritylresin, Fmoc-Leu-2-chlorotritylresin,Fmoc-Glu(OtBu)-2-chlorotritylresin, Fmoc-Asp(OtBu)-2-chlorotritylresin,.Fmoc-Phe-2-chlorotritylresin, Fmoc-Gln(Trt)-2-chlorotritylresin,Fmoc-Ser (OtBu) -2-chlorotritylresin, Fmoc-Val-2-chlorotritylresin,Fmoc-Thr(OtBu) -2-chlorotritylresin and Fmoc-Ile-2-chlorotritylresin.

Synthesis of the Fully Protected Peptide Fragment

The synthesis was carried out using a Syro-peptide synthesizer(Multisyntech) using 24 to 96 reaction vessels. In each vessel wereplaced 60 mg (weight of the resin before loading) of the above resin.The following reaction cycles were programmed and carried out:

Step Reagent Time 1 CH₂Cl₂, wash and swell (manual) 3 × 1 min. 2 DMF,wash and swell 1 × 5 min. 3 40% piperidine/DMF 1 × 5 min. 4 DMF, wash 5× 2 min. 5 5 equiv. Fmoc amino acid/DMF +5 eq. HBTU +5 eq. HOBt +5 eq.DIEA 1 × 120 min. 6 DMF, wash 4 × 2 min. 7 CH₂Cl₂, wash (at the end ofthe synthesis) 3 × 2 min.

Steps 3 to 6 are repeated to add each amino-acid.

After the synthesis of the fully protected peptide fragment had beenterminated, then subsequently either Procedure A or Procedure B, asdescribed hereinbelow, was adopted, depending on whether not interstrandlinkages (i.e. disulfide (3-strand linkages) were to be formed.

Procedure A: Cyclization and Work up of Backbone Cyclized PeptidesCleavage of the Fully Protected Peptide Fragment

After completion of the synthesis, the resin was suspended in 1 ml (0.39mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes, filtered and the filtratewas neutralized with 1 ml (1.17 mMol, 3 eq.) of 20% DIEA in CH₂Cl₂(v/v). This procedure was repeated twice to ensure completion of thecleavage. An aliquot (200 μL) of the filtrate was fully deprotected with0.5 ml of the cleavage mixture containing 95% trifluoroacetic acid(TFA), 2.5% water and 2.5% triisopropylsilane (TIS) and analysed byreverse phase-LC MS to monitor the efficiency of the linear peptidesynthesis.

Cyclization of the Linear Peptide

The fully protected linear peptide was dissolved in DMF (8 ml, conc. 10mg/ml). Two eq. of HATU (0.72 mMol) in 1 ml of DMF and 4 eq. of DIEA(1.44 mMol) in 1 ml of DMF were added, and the mixture was stirred atroom temperature for 16 h. The volatile was evaporated to dryness. Thecrude cyclized peptide was dissolved in 7 ml of CH₂Cl₂ and extractedwith 10% acetonitrile in water (4.5 ml) three times. The CH₂Cl₂ layerwas evaporated to dryness.

Deprotection and Purification of the Cyclic Peptide

The cyclic peptide obtained was dissolved in 3 ml of the cleavagemixture containing 95% trifluoroacetic acid (TFA), 2.5% water and 2.5%triisopropylsilane (TIS). The mixture was left to stand at 20° C. for2.5 hours and then concentrated under vacuum. The crude peptide wasdissolved in 20% AcOH in water (7 ml) and extracted withdiisopropylether (4 ml) three times. The aqueous layer was collected andevaporated to dryness, and the residue was purified by preparativereverse phase LC-MS.

After lyophilisation the products were obtained as white powders andanalysed by LC-MS. The analytical data comprising purity afterpreparative HPLC and ESI-MS are shown in Table 1.

Analytical Method:

Analytical HPLC retention times (RT, in minutes) were determined usingan Jupiter Proteo 90A, 150×2.0 mm, (cod. 00F4396—B0-Phenomenex) with thefollowing solvents A (H₂O +0.1% TFA) and B (CH₃CN+0.1% TFA) and thegradient: 0 min: 95%A, 5%B; 20 min: 40%A 60%B; 21-23 min: 0%A, 100%B;23.1-30 min: 95% A, 5%B.

Procedure B: Cyclization and Work Up of Backbone Cyclized Peptideshaving Disulfide β-Strand Linkages

Formation of Disulfide β-Strand Linkage

After completion of the synthesis, the resin was swelled in 3 ml of dryDMF for 1 h. Then 10 eq. of iodine solution in DMF (6 ml) were added tothe reactor, followed by stirring for 1.5 h. The resin was filtered anda fresh solution of iodine (10 eq.) in DMF (6 ml) was added, followed bystirring for another 3 h. The resin was filtered and washed with DMF(3×) and CH₂Cl₂ (3×).

Backbone Cyclization, Cleavage and Purification of the Peptide

After formation of the disulfide β-strand linkage, the resin wassuspended in 1 ml (0.39 mMol) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutesand filtered, and the filtrate was neutralized with 1 ml (1.17 mMol, 3eq.) of 20% DIEA in CH₂Cl₂ (v/v). This procedure was repeated twice toensure completion of the cleavage. The resin was washed with 2 ml ofCH₂Cl₂. The CH₂Cl₂ layer was evaporated to dryness.

The fully protected linear peptide was solubilized in 8 ml of dry DMF.Then 2 eq. of HATU in dry DMF (1ml) and 4 eq. of DIPEA in dry DMF (1 ml)were added to the peptide, followed by stirring for 16 h. The volatileswere evaporated to dryness. The crude cyclized peptide was dissolved in7 ml of CH₂Cl₂ and extracted with 10% acetonitrile in water (4.5 ml)three times. The CH₂Cl₂ layer was evaporated to dryness. To deprotectthe peptide fully, 3 ml of cleavage cocktail TFA:TIS:H₂O (95:2.5:2.5)were added, and the mixture was kept for 2.5 h. The volatile wasevaporated to dryness and the crude peptide was dissolved in 20% AcOH inwater (7 ml) and extracted with diisopropyl ether (4 ml) for threetimes. The aqueous layer was collected and evaporated to dryness, andthe residue was purified by preparative reverse phase LC-MS.

After lyophilisation the products were obtained as white powders andanalysed by ESI-MS analytical method as described above. The analyticaldata comprising purity after preparative HPLC and ESI-MS are shown inTable 1.

Examples 1-45, 52-63, 65-67, 70-71, 75-114, 129, 131-162 and 179-196 areshown in Table 1. The peptides were synthesized starting with the aminoacid Pro which was grafted to the resin. Starting resin wasFmoc-Pro-2-chlorotrityl resin, which was prepared as described above.The linear peptides were synthesized on solid support according to theprocedure described above in the following sequence:Resin-Pro-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Ex. 1-6, 9-45,52-63, 65-67, 70-71, 75-103 112-114, 129, 131, 133, 136-138, 140-141,143-146, 148-153, 155, 157-162 and 179-196 were cleaved from the resin,subjected to the disulfide bridge formation, cyclized, deprotected andpurified as indicated in procedure B. Ex. 82, 123, 149, 159, 161 and 178were cleaved from the resin as indicated in procedure B. The disulfidebridges were formed using the following procedure:

The crude product was solubilized in an ammonium acetate buffer 0.1M (pHadjusted to 8) (concentration: 1 mg of crude product per ml). Themixture was stirred at room temperature in presence of air. The reactionwas monitored by reverse phase LC-MS. After reaction completion, thesolution was evaporated to dryness and the residue purified bypreparative reverse phase LC-MS.

The cyclization of the backbone was performed as indicated in procedureA. The deprotection was performed using the following procedure:

To deprotect the peptide fully, 5 ml of cleavage cocktailTFA:H₂O:Phenol:Thioanisol: Ethanedithiol (82.5:5:5:5:2.5) were added,and the mixture was kept for 5 h at room temperature. The peptide wasprecipitated by addition of cold diethylether (10ml). Aftercentrifugation, the supernatant phase was removed. The precipitate waswashed three times with 5 ml of diethylether and was purified bypreparative reverse phase LC-MS.

After lyophilisation the products were obtained as white powders andanalysed by ESI-MS analytical method as described above.

Ex. 7, 8, 104-111, 132, 134, 135, 139, 142, 147, 154 and 156 werecleaved from the resin, cyclized, deprotected and purified as indicatedin procedure A.

HPLC -retention times (minutes) were determined using the analyticalmethod as described above:

Ex. 1 (15.37), Ex. 2 (11.54), Ex. 3 (7.82), Ex. 4 (8.62), Ex. 5 (16.51),Ex. 6 (13.67), Ex. 7 (3.61), Ex. 8 (4.11), Ex. 9 (5.82), Ex. 10 (7.98),Ex. 11 (8.38), Ex. 12 (6.80), Ex. 13 (7.41), Ex. 14 (6.20), Ex. 15(8.68), Ex. 16 (9.82); Ex. 17 (5.59), Ex. 20 (7.32), Ex. 21 (8.66), Ex.22 (8.68), Ex. 23 (12.66), Ex. 24 (8.67), Ex. 25 (7.53), Ex. 26 (9.02),Ex. 27 (8.06), Ex. 28 (9.62), Ex. 29 (8.78), Ex. 30 (10.49), Ex. 31(5.50), Ex. 32 (7.45), Ex. 33 (8.39), Ex. 34 (10.16), Ex. 35 (9.04), Ex.36 (10.98), Ex. 37 (7.56), Ex. 38 (9.29), Ex. 39 (8.32), Ex. 40 (10.11),Ex. 41 (7.23), Ex. 42 (8.83), Ex. 43 (7.92), Ex. 44 (9.87), Ex. 45(8.26), Ex. 52 (6.20), Ex. 53 (8.68), Ex 54 (9.82), Ex. 55 (5.59), Ex.56 (6.06), Ex. 57 (6.47), Ex. 58 (7.32), Ex. 59 (8.68), Ex. 60 (10.66),Ex. 61 (8.54), Ex. 62 (9.83), Ex. 63 (16.54), Ex. 65 (15.71), Ex. 66(17.50), Ex. 67 (15.87), Ex. 70 (12.87), Ex. 71 (13.48), Ex. 75 (14.22),Ex. 76 (4.47), Ex. 77 (5.15), Ex. 78 (10.93), Ex. 79 (10.70), Ex. 80(12.09), Ex. 81 (11.63), Ex. 82 (5.71), Ex. 83 (5.45), Ex. 84 (11.14),Ex. 85 (10.90), Ex. 86 (13.78), Ex. 87 (13.98), Ex. 88 (14.35), Ex. 89(15.21), Ex. 90 (14.72), Ex. 91 (11.97), Ex. 92 (11.77), Ex. 93 (15.25),Ex. 94 (14.61), Ex. 95 (20.46), Ex. 96 (15.08), Ex. 97 (20.78), Ex. 98(18.28), Ex. 99 (14.62), Ex. 100 (13.90), Ex. 101 (13.76), Ex. 102(20.53), Ex. 103 (14.14), Ex. 104 (11.60), Ex. 105 (11.90), Ex. 106(11.63), Ex. 107 (11.78), Ex. 108 (13.03), Ex. 109 (15.22), Ex. 110(12.40), Ex. 111 (12.10), Ex. 112 (5.49), Ex. 113 (5.67), Ex. 114(5.55), Ex. 129 (17.22), Ex. 131 (11.97), Ex. 132 (13.56), Ex. 133(14.57), Ex. 134 (14.72), Ex. 135 (17.53), Ex. 136 (18.28), Ex. 137(14.72), Ex. 138 (14.35), Ex. 139 (15.40), Ex. 140 (11.14), Ex. 141(5.71), Ex. 142 (13.97), Ex. 143 (13.94), Ex. 144 (15.08), Ex. 145(20.87), Ex. 146 (17.91), Ex. 147 (17.11), Ex. 148 (7.83), Ex. 149(16.22), Ex. 150 (20.09), Ex. 151 (20.72), Ex. 152 (21.38), Ex. 153(17.97), Ex. 154 (16.58), Ex. 155 (19.46), Ex. 156 (15.66), Ex. 157(22.04), Ex. 158 (15.65), Ex. 159 (17.89), Ex. 160 (18.72), Ex. 161(19.91), Ex. 162 (17.79), Ex. 179 (4.25), Ex. 180 (11.43), Ex. 181(12.30), Ex. 182 (12.83), Ex. 183 (10.51), Ex. 184 (12.12), Ex. 185(10.14), Ex. 186 (10.09), Ex. 187 (10.14), Ex. 188 (10.65), Ex. 189(10.73), Ex. 190 (10.10), Ex. 191 (10.17), Ex. 192 (10.19), Ex. 193(11.02), Ex. 194 (9.92), Ex. 195 (10.74), Ex. 196 (9.94).

Example 46 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Asp(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 46 (8.94).

Example 47 is shown in Table 1. The peptide was synthesized startingwith the amino acid Asp which was grafted to the resin. Starting resinwas Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Asp(OtBu)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methodas described above:

Ex. 47 (7.29).

Example 48 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro(5RPhe) which was grafted to the resin. Startingresin was Fmoc-Pro(5RPhe)-2-chlorotrityl resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-Pro(5RPhe)-^(D)Pr o-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.HPLC-retention time (minutes) was determined using the analyticaldescribed above:

Ex. 48 (10.07).

Example 49 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Ala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 49 (8.09);

Example 50 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Ile-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analyticaldescribed above:

Ex. 50 (9.78).

Example 51 is shown in Table 1. The peptide was synthesized startingwith the amino acid Leu which was grafted to the resin. Starting resinwas Fmoc-Leu-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Leu-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 51 (8.94);

Example 64 is shown in Table 1. The peptide was synthesized startingwith the amino acid Glu which was grafted to the resin. Starting resinwas Fmoc-Glu(OtBut)-2-chlorotrityl resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-Glu(OtBu)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 64 (13.17).

Example 68 is shown in Table 1. The peptide was synthesized startingwith the amino acid Asp which was grafted to the resin. Starting resinwas Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Asp(OtBu)-^(D)Ala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 68 (12.44).

Example 69 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence: ResinPro-^(D)Asn(Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 69 (12.97).

Example 72 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Thr(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 72 (13.34).

Example 73 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Ile-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 73 (9.78).

Example 74 is shown in Table 1. The peptide was synthesized startingwith the amino acid Leu which was grafted to the resin. Starting resinwas Fmoc-Leu-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Leu-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 74 (8.94).

Example 115 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Asp(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 115 (4.82).

Example 116 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Phe-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 116 (5.98).

Example 117 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Arg(Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 117 (4.48).

Example 118 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Ser(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 118 (4.73).

Example 119 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Val-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 119 (5.47).

Example 120 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Pip-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the gradient method 1described above:

Ex. 120 (5.48).

Example 121 is shown in Table 1. The peptide was synthesized startingwith the amino acid Asp which was grafted to the resin. Starting resinwas Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Asp(OtBu)-^(D)Pro-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridge was formed, and the peptide was cleavedfrom the resin, cyclized, deprotected and purified as indicated inprocedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 121 (4.56).

Examples 122 and 167 are shown in Table 1. The peptides were synthesizedstarting with the amino acid Phe which was grafted to the resin.Starting resin was Fmoc-Phe-2-chlorotrityl resin, which was prepared asdescribed above. The linear peptides were synthesized on solid supportaccording to procedure described above in the following sequence:Resin-Phe-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 122 (5.75); 167 (5.75).

Examples 123, 164, 169, 170, 172, 173, 175, 177 and 178 are shown inTable 1. The peptides were synthesized starting with the amino acid Glnwhich was grafted to the resin. Starting resin wasFmoc-Gln(Trt)-2-chlorotrityl resin, which was prepared as describedabove. The linear peptides were synthesized on solid support accordingto procedure described above in the following sequence:Resin-Gln(Trt)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 123 (4.35), 164 (13.20), 169 (16.81), 170 (14.57), 172 (16.78), 173(13.57), 175 (15.94), 177 (16.78), 178 (17.45).

Example 124 is shown in Table 1. The peptide was synthesized startingwith the amino acid Ser which was grafted to the resin. Starting resinwas Fmoc-Ser(OtBu)-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Ser(OtBu)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 124 (4.46).

Example 125 is shown in Table 1. The peptide was synthesized startingwith the amino acid Val which was grafted to the resin. Starting resinwas Fmoc-Val-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Val-^(D)Pro-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 125 (18.42).

Example 126 is shown in Table 1. The peptide was synthesized startingwith the amino acid Thr which was grafted to the resin. Starting resinwas Fmoc-Thr(OtBu)-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Thr(OtBu)-^(D)Thr(OtBu)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridge was formed, and the peptide was cleavedfrom the resin, cyclized, deprotected and purified as indicated inprocedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 126 (4.35).

Examples 127, 163, 165 and 174 are shown in Table 1. The peptides weresynthesized starting with the amino acid Glu which was grafted to theresin. Starting resin was Fmoc-Glu(OtBu)-2-chlorotrityl resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence:Resin-Glu(OtBu)-^(D)Lys(Boc)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridge was formed, and the peptide was cleavedfrom the resin, cyclized, deprotected and purified as indicated inprocedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 127 (4.11), 163 (14.93), 165 (14.40), 174 (12.73).

Example 128 is shown in Table 1. The peptide is synthesized startingwith the amino acid Thr which was grafted to the resin. Starting resinwas Fmoc-Thr(OtBu)-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Thr(OtBu)-^(D)Phe-P11-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridge was formed, and the peptide was cleavedfrom the resin, cyclized, deprotected and purified as indicated inprocedure B.

HPLC-retention time (minutes) was determined using the gradient method 1described above:

Ex. 128 (5.26).

Example 130 is shown in Table 1. The peptide was synthesized startingwith the amino acid Pro which was grafted to the resin. Starting resinwas Fmoc-Pro-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Pro-^(D)Ala-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 130 (14.79).

Example 166 is shown in Table 1. The peptide was synthesized startingwith the amino acid Ile which was grafted to the resin. Starting resinwas Fmoc-Ile-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Ile-^(D)Phe-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafter thedisulfide bridge was formed, and the peptide was cleaved from the resin,cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 166 (16.80).

Example 168 is shown in Table 1. The peptide was synthesized startingwith the amino acid Asp which was grafted to the resin. Starting resinwas Fmoc-Asp(OtBu)-2-chlorotrityl resin, which was prepared as describedabove. The linear peptide was synthesized on solid support according toprocedure described above in the following sequence:Resin-Asp(OtBu)-^(D)Pro-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1. Thereafterthe disulfide bridge was formed, and the peptide was cleaved from theresin, cyclized, deprotected and purified as indicated in procedure B.

HPLC-retention time (minutes) was determined using the analyticaldescribed above:

Ex. 168 (4.56).

Examples 171 and 176 are shown in Table 1. The peptides were synthesizedstarting with the amino acid Gln which was grafted to the resin.Starting resin was Fmoc-Gln(Trt)-2-chlorotrityl resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence: Resin-Gln(TrO-^(D)Gln(Trt)-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1.Thereafter the disulfide bridge was formed, and the peptide was cleavedfrom the resin, cyclized, deprotected and purified as indicated inprocedure B.

HPLC-retention time (minutes) was determined using the analytical methoddescribed above:

Ex. 171 (15.40), 176 (13.67).

TABLE 1 Examples Ex- ample Sequ.ID P1 P2 P3 P4 P5 P6 P7 P8 P9 P10 P11Template Purity%^(a)) [M + H]   1 SEQ ID NO: 1 Phe Cys Thr Lys Ser GluPro Pro Ile Cys Thr ^(D)Pro^(L)Pro 95 1385.7   2 SEQ ID NO: 2 Phe CysThr Lys Ser Asp Pro Pro Ile Cys Asp ^(D)Pro^(L)Pro 93 1399.5   3SEQ ID NO: 3 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro95 1398.5   4 SEQ ID NO: 4 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser^(D)Pro^(L)Pro 95 1371.1   5 SEQ ID NO: 5 Phe Cys Thr Lys Ser Asp ProPro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1447.5   6 SEQ ID NO: 6 Tyr Cys ThrLys Ser Asp Pro Pro Ile Cys Thr ^(D)Pro^(L)Pro 95 1401.7   7SEQ ID NO: 7 Arg Glu Thr Lys Ser Asp Pro Pro Ile Arg Phe ^(D)Pro^(L)Pro95 1521.2   8 SEQ ID NO: 8 Arg Nle Thr Lys Ser Asp Pro Pro Ile Nle Phe^(D)Pro^(L)Pro 95 1462.4   9 SEQ ID NO: 9 4AmPhe Cys Thr Lys Ser Asp ProPro Ile Cys Ser ^(D)Pro^(L)Pro 92 1386.9  10 SEQ ID NO: 10 Nle Cys ThrLys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro 93 1337.8  11SEQ ID NO: 11 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro95 1363.8  12 SEQ ID NO: 12 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Arg^(D)Pro^(L)Pro 95 1432.7  13 SEQ ID NO: 13 2Cl-Phe Cys Thr Lys Ser AspPro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1474.5  14 SEQ ID NO: 14 Ile CysThr Lys Ser Asp Pro Ala Ile Cys Arg ^(D)Pro^(L)Pro 93 1380.5  15SEQ ID NO: 15 Phe Cys Thr Lys Ser Asp Pro Pro Nle Cys Ser ^(D)Pro^(L)Pro95 1371.8  16 SEQ ID NO: 16 Phe Cys Thr Lys Ser Asp Pro Pro Cha Cys Ser^(D)Pro^(L)Pro 95 1411.6  17 SEQ ID NO: 17 Ile Cys Thr Lys Ser Asp ProPro Gln Cys Arg ^(D)Pro^(L)Pro 95 1421.6  18 SEQ ID NO: 18 Ile Cys ThrLys Ser Asp Pro Pro Tyr Cys Arg ^(D)Pro^(L)Pro 89 1456.6  19SEQ ID NO: 19 Ile Cys Thr Lys Ser Asp Pro Pro Nle Cys Arg ^(D)Pro^(L)Pro95 1476.6  20 SEQ ID NO: 20 Ile Cys Thr Lys Ser Asp Pro Pro Cha Cys Arg^(D)Pro^(L)Pro 95 1446.5  21 SEQ ID NO: 21 Phe Cys Thr Lys Ser Glu ProPro Ile Cys Ser ^(D)Pro^(L)Pro 95 1385.8  22 SEQ ID NO: 22 Ile Cys ThrNle Ser Asp Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1391.6  23SEQ ID NO: 23 Phe Cys Thr Nle Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro95 1432.7  24 SEQ ID NO: 24 Phe Cys Thr Lys AlloThr Asp Pro Pro Ile CysSer ^(D)Pro^(L)Pro 95 1385.7  25 SEQ ID NO: 25 Phe Cys Thr Lys Dpr AspPro Pro Ile Cys Ser ^(D)Pro^(L)Pro 95 1370.9  26 SEQ ID NO: 26 Tyr CysThr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1463.8  27SEQ ID NO: 27 hPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn^(D)Pro^(L)Pro 95 1412.6  28 SEQ ID NO: 28 hPhe Cys Thr Lys Ser Asp ProPro Ile Cys Thr ^(D)Pro^(L)Pro 95 1399.7  29 SEQ ID NO: 29 hPhe Cys ThrLys Ser Asp Pro Pro Ile Cys Asp ^(D)Pro^(L)Pro 95 1413.6  30SEQ ID NO: 30 hPhe Cys Thr Lys Ser Asp Pro Pro Ile Cys Tyr^(D)Pro^(L)Pro 95 1461.7  31 SEQ ID NO: 31 4AmPhe Cys Thr Lys Ser AspPro Pro Ile Cys Asn ^(D)Pro^(L)Pro 91 1413.8  32 SEQ ID NO: 32 4AmPheCys Thr Lys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 93 1462.7  33SEQ ID NO: 33 Cha Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro94 1404.8  34 SEQ ID NO: 34 Cha Cys Thr Lys Ser Asp Pro Pro Ile Cys Thr^(D)Pro^(L)Pro 95 1391.7  35 SEQ ID NO: 35 Cha Cys Thr Lys Ser Asp ProPro Ile Cys Asp ^(D)Pro^(L)Pro 95 1405.8  36 SEQ ID NO: 36 Cha Cys ThrLys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1453.8  37SEQ ID NO: 37 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro95 1390.7  38 SEQ ID NO: 38 Chg Cys Thr Lys Ser Asp Pro Pro Ile Cys Thr^(D)Pro^(L)Pro 95 1377.6  39 SEQ ID NO: 39 Chg Cys Thr Lys Ser Asp ProPro Ile Cys Asp ^(D)Pro^(L)Pro 95 1391.6  40 SEQ ID NO: 40 Chg Cys ThrLys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1439.6  41SEQ ID NO: 41 Nle Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn ^(D)Pro^(L)Pro95 1364.7  42 SEQ ID NO: 42 Nle Cys Thr Lys Ser Asp Pro Pro Ile Cys Thr^(D)Pro^(L)Pro 93 1351.7  43 SEQ ID NO: 43 Nle Cys Thr Lys Ser Asp ProPro Ile Cys Asp ^(D)Pro^(L)Pro 95 1365.7  44 SEQ ID NO: 44 Nle Cys ThrLys Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro 95 1413.6  45SEQ ID NO: 45 2Cl-Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Asn^(D)Pro^(L)Pro 95 1432.6  46 SEQ ID NO: 46 Phe Cys Thr Lys Ser Asp ProPro Ile Cys Ser ^(D)Asp^(L)Pro 95 1389.6  47 SEQ ID NO: 47 Phe Cys ThrLys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Asp 95 1389.6  48SEQ ID NO: 48 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Pro95 1447.5   (5RPhe)  49 SEQ ID NO: 49 Phe Cys Thr Lys Ser Asp Pro ProIle Cys Ser ^(D)Ala^(L)Pro 95 1345.6  50 SEQ ID NO: 50 Phe Cys Thr LysSer Asp Pro Pro Ile Cys Ser ^(D)Ile^(L)Pro 94 1387.9  51 SEQ ID NO: 51Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Leu 94 1395.7  52SEQ ID NO: 52 Ile Cys Thr Lys Ser Asp Pro Ala Ile Cys Arg ^(D)Pro^(L)Pro93 1380.7  53 SEQ ID NO: 53 Phe Cys Thr Lys Ser Asp Pro Pro Nle Cys Ser^(D)Pro^(L)Pro 95 1371.8  54 SEQ ID NO: 54 Phe Cys Thr Lys Ser Asp ProPro Cha Cys Ser ^(D)Pro^(L)Pro 95 1411.6  55 SEQ ID NO: 55 Ile Cys ThrLys Ser Asp Pro Pro Gln Cys Arg ^(D)Pro^(L)Pro 95 1421.6  56SEQ ID NO: 56 Ile Cys Thr Lys Ser Asp Pro Pro Tyr Cys Arg ^(D)Pro^(L)Pro89 1456.5  57 SEQ ID NO: 57 Ile Cys Thr Lys Ser Asp Pro Pro Nle Cys Arg^(D)Pro^(L)Pro 94 1406.6  58 SEQ ID NO: 58 Ile Cys Thr Lys Ser Asp ProPro Cha Cys Arg ^(D)Pro^(L)Pro 95 1446.5  59 SEQ ID NO: 59 Ile Cys ThrNle Ser Asp Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1391.6  60SEQ ID NO: 60 Phe Cys Thr Nle Ser Asp Pro Pro Ile Cys Tyr ^(D)Pro^(L)Pro95 1432.7  62 SEQ ID NO: 62 1-Nal Cys Thr Lys Ser Asp Pro Pro Ile CysSer ^(D)Pro^(L)Pro 95 1421.9  63 SEQ ID NO: 63 Chg Cys Thr Lys Ser AspPro Pro Nle Cys Tyr ^(D)Pro^(L)Pro 95 1439.  64 SEQ ID NO: 64 Phe CysThr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Pro^(L)Glu 95 1403.8  65SEQ ID NO: 65 Chg Cys Thr Lys Ser Asp Pro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro95 1489.5  66 SEQ ID NO: 66 Chg Cys Thr Lys Ser Asp Pro Pro Cha Cys Tyr^(D)Pro^(L)Pro 95 1479.6  67 SEQ ID NO: 67 Chg Cys Thr Lys AlloThr AspPro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro 95 1503.6  68 SEQ ID NO: 68 Phe CysThr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Ala^(L)Asp 95 1363.6  69SEQ ID NO: 69 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Asn^(L)Pro90 1388.8  70 SEQ ID NO: 70 4AmPhe Cys Thr Lys Ser Asp Pro Pro Cha CysAsn ^(D)Pro^(L)Pro 92 1454.5  71 SEQ ID NO: 71 Chg Cys Thr Lys Ser AspPro Pro Cha Cys Arg ^(D)Pro^(L)Pro 95 1472.6  72 SEQ ID NO: 72 Phe CysThr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Thr^(L)Pro 95 1375.6  73SEQ ID NO: 73 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser ^(D)Ile^(L)Pro94 1387.9  74 SEQ ID NO: 74 Phe Cys Thr Lys Ser Asp Pro Pro Ile Cys Ser^(D)Pro^(L)Leu 94 1387.9  75 SEQ ID NO: 75 Arg Cys Thr Lys Ser Asp ProPro Ile Cys Phe ^(D)Pro^(L)Pro 95 1440.5  76 SEQ ID NO: 76 Ile Cys ThrAla Ser Leu Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1369.3  77SEQ ID NO: 77 Nle Cys Thr Thr Ser Ile Pro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro95 1434.3  78 SEQ ID NO: 78 Nle Cys Thr Abu Ser Ile Pro Pro Gln Cys Tyr^(D)Pro^(L)Pro 95 1383.6  79 SEQ ID NO: 79 Nle Cys Thr Ala Ser Nle ProPro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1369.8  80 SEQ ID NO: 80 Nle Cys ThrAla Ser Aoc Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1397.6  81SEQ ID NO: 81 Nle Cys Thr Ala Ser OctG Pro Pro Gln Cys Tyr^(D)Pro^(L)Pro 95 1425.6  82 SEQ ID NO: 82 Nle Cys Thr Ala Ser Cha ProPro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1409.5  83 SEQ ID NO: 83 Nle Cys ThrAla Ser hLeu Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1383.6  84SEQ ID NO: 84 Nle Cys Thr Ala Ser Chg Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro95 1395.7  85 SEQ ID NO: 85 Nle Cys Thr Ala Ser t-BuAla Pro Pro Gln CysTyr ^(D)Pro^(L)Pro 95 1383.6  86 SEQ ID NO: 86 Nle Cys Ala Ala Ser IlePro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1340.1  87 SEQ ID NO: 87 Nle CysAbu Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1354.0  88SEQ ID NO: 88 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro95 1488.6   (4NHCOPhe)  89 SEQ ID NO: 89 Nle Cys Thr Ala Ser Ile Pro ProPhe Cys Tyr ^(D)Pro^(L)Pro 88 1388.7  90 SEQ ID NO: 90 Nle Cys Thr AlaSer Ile Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 95 1353.6  91 SEQ ID NO: 91Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1334.5  92SEQ ID NO: 92 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Arg ^(D)Pro^(L)Pro56 1362.6  93 SEQ ID NO: 93 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Ser^(D)Pro^(L)Pro 95 1293.7  94 SEQ ID NO: 94 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Nle ^(D)Pro^(L)Pro 95 1319.5  95 SEQ ID NO: 95 Nle Cys ThrAla Ser Ile Pro Pro Gln Cys 2- ^(D)Pro^(L)Pro 94 1404.0 Nal  96SEQ ID NO: 96 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys 2Cl-^(D)Pro^(L)Pro 94 1387.8 Phe  97 SEQ ID NO: 97 Nle Cys Thr Ala Ser IlePro Pro Gln Cys Cha ^(D)Pro^(L)Pro 95 1359.8  98 SEQ ID NO: 98 Nle CysThr Ala Ser Ile Pro Pro Gln Cys Phg ^(D)Pro^(L)Pro 95 1359.9  99SEQ ID NO: 99 Aoc Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro93 1397.4 100 SEQ ID NO: 100 hLeu Cys Thr Ala Ser Ile Pro Pro Gln CysTyr ^(D)Pro^(L)Pro 95 1383.4 101 SEQ ID NO: 101 Chg Cys Thr Ala Ser IlePro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 87 1395.6 102 SEQ ID NO: 102 OctG CysThr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1425.5 103SEQ ID NO: 103 hPhe Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Pro^(L)Pro 95 1417.5 104 SEQ ID NO: 104 Nle Glu Thr Ala Ser Ile ProPro Gln Lys Tyr ^(D)Pro^(L)Pro 95 1422.8 105 SEQ ID NO: 105 Nle Glu ThrAla Ser Ile Pro Pro Gln Arg Tyr ^(D)Pro^(L)Pro 95 1450.9 106SEQ ID NO: 106 Nle Thr Thr Ala Ser Ile Pro Pro Gln Lys Tyr^(D)Pro^(L)Pro 95 1394.7 107 SEQ ID NO: 107 Nle Gln Thr Ala Ser Ile ProPro Gln Arg Tyr ^(D)Pro^(L)Pro 90 1449.8 108 SEQ ID NO: 108 Nle Thr ThrAla Ser Ile Pro Pro Gln Met Tyr ^(D)Pro^(L)Pro 96 1397.7 109SEQ ID NO: 109 Nle Gln Thr Ala Ser Ile Pro Pro Gln Thr Tyr^(D)Pro^(L)Pro 95 1394.7 110 SEQ ID NO: 110 Nle Thr Thr Ala Ser Ile ProPro Gln Gln Tyr ^(D)Pro^(L)Pro 81 1394.6 111 SEQ ID NO: 111 Nle Gln ThrAla Ser Ile Pro Pro Gln Ser Tyr ^(D)Pro^(L)Pro 95 1380.7 112SEQ ID NO: 112 Nle Cys Thr Ala Ser C5a1 Pro Pro Gln Cys Tyr^(D)Pro^(L)Pro 85 1413.8 113 SEQ ID NO: 113 Nle Cys Thr Ala Ser Leu ProPro Tyr Cys Tyr ^(D)Pro^(L)Pro 95 1404.7 114 SEQ ID NO: 114 Ile Cys ThrAla Ser Leu Pro Pro Tyr Cys Tyr ^(D)Pro^(L)Pro 95 1404.7 115SEQ ID NO: 115 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Asp^(L)Pro 95 1387.8 116 SEQ ID NO: 116 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Tyr ^(D)Phe^(L)Pro 95 1419.9 117 SEQ ID NO: 117 Nle Cys ThrAla Ser Ile Pro Pro Gln Cys Tyr ^(D)Arg^(L)Pro 95 1428.6 118SEQ ID NO: 118 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Ser^(L)Pro 95 1359.9 119 SEQ ID NO: 119 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Tyr ^(D)Val^(L)Pro 95 1371.8 120 SEQ ID NO: 120 Nle Cys ThrAla Ser Ile Pro Pro Gln Cys Tyr ^(D)Pic^(L)Pro 95 1383.7 121SEQ ID NO: 121 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Pro^(L)Asp 95 1387.9 122 SEQ ID NO: 122 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Tyr ^(D)Pro^(L)Phe 95 1419.9 123 SEQ ID NO: 123 Nle Cys ThrAla Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Gln 95 1400.6 124SEQ ID NO: 124 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Pro^(L)Ser 95 1359.5 125 SEQ ID NO: 125 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Tyr ^(D)Pro^(L)Val 95 1371.8 126 SEQ ID NO: 126 Nle Cys ThrAla Ser Ile Pro Pro Gln Cys Tyr ^(D)Thr^(L)Thr 95 1377.4 127SEQ ID NO: 127 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Lys^(L)Glu 95 1433.5 128 SEQ ID NO: 128 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Tyr ^(D)Phe^(L)Thr 95 1423.5 129 SEQ ID NO: 129 Nle Cys ThrAla Ser OctG Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 91 1390.4 130SEQ ID NO: 130 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Ala^(L)Pro 95 1343.5 131 SEQ ID NO: 131 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Gln ^(D)Pro^(L)Pro 95 1334.5 132 SEQ ID NO: 132 hPhe Glu ThrAla Ser Ile Pro Pro Gln Lys Tyr ^(D)Pro^(L)Pro 95 1470.6 133SEQ ID NO: 133 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Gln^(D)Pro^(L)Pro 95 1440.5 134 SEQ ID NO: 134 hPhe Thr Thr Ala Ser Ile ProPro Gln Gln Tyr ^(D)Pro^(L)Pro 95 1442.5 135 SEQ ID NO: 135 Nle Thr ThrAla Ser OctG Pro Pro Gln Gln Tyr ^(D)Pro^(L)Pro 88 1450.7 136SEQ ID NO: 136 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Phg^(D)Pro^(L)Pro 95 1339.9 137 SEQ ID NO: 137 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Phe ^(D)Pro^(L)Pro 95 1353.6 138 SEQ ID NO: 138 Nle Cys ThrAla Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1488.6 (4NHCOPhe) 139SEQ ID NO: 139 Nle Thr Thr Ala Ser Cha Pro Pro Gln Gln Tyr^(D)Pro^(L)Pro 95 1434.8 140 SEQ ID NO: 140 Nle Cys Thr Ala Ser Chg ProPro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1395.7 141 SEQ ID NO: 141 Nle Cys ThrAla Ser Cha Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1409.5 142SEQ ID NO: 142 hPhe Gln Thr Ala Ser Ile Pro Pro Gln Thr Tyr^(D)Pro^(L)Pro 91 1406.5 143 SEQ ID NO: 143 hPhe Cys Thr Ala Ser Ile ProPro Gln Cys Gln ^(D)Pro^(L)Pro 94 1383.5 144 SEQ ID NO: 144 Nle Cys ThrAla Ser Ile Pro Pro Gln Cys 2Cl- ^(D)Pro^(L)Pro 94 1387.8 Phe 145SEQ ID NO: 145 OctG Cys Thr Ala Ser Ile Pro Pro Gln Cys Phe^(D)Pro^(L)Pro 95 1409.4 146 SEQ ID NO: 146 hPhe Cys Thr Ala Ser Ile ProPro Gln Cys Phe ^(D)Pro^(L)Pro 95 1401.5 147 SEQ ID NO: 147 OctG Thr ThrAla Ser Ile Pro Pro Gln Gln Tyr ^(D)Pro^(L)Pro 95 1450.9 148SEQ ID NO: 148 OctG Cys Thr Ala Ser OctG Pro Pro Gln Cys Gln^(D)Pro^(L)Pro 95 1446.6 149 SEQ ID NO: 149 OctG Cys Thr Ala Ser Ile ProPro Gln Cys Gln ^(D)Pro^(L)Pro 95 1390.4 150 SEQ ID NO: 150 OctG Cys ThrAla Ser Cha Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1465.6 151SEQ ID NO: 151 OctG Cys Thr Ala Ser OctG Pro Pro Gln Cys Gln^(D)Pro^(L)Pro 94 1565.7 (4NHCOPhe) 152 SEQ ID NO: 152 hPhe Cys Thr AlaSer OctG Pro Pro Gln Cys Phe ^(D)Pro^(L)Pro 95 1457.6 153 SEQ ID NO: 153hPhe Cys Thr Ala Ser OctG Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 95 1438.5154 SEQ ID NO: 154 OctG Gln Thr Ala Ser Ile Pro Pro Gln Thr Tyr^(D)Pro^(L)Pro 93 1450.9 155 SEQ ID NO: 155 hPhe Cys Thr Ala Ser Cha ProPro Gln Cys Phe ^(D)Pro^(L)Pro 90 1441.5 156 SEQ ID NO: 156 OctG Glu ThrAla Ser Ile Pro Pro Gln Lys Tyr ^(D)Pro^(L)Pro 95 1478.7 157SEQ ID NO: 157 OctG Cys Thr Ala Ser Cha Pro Pro Gln Cys Phe^(D)Pro^(L)Pro 95 1449.8 158 SEQ ID NO: 158 hPhe Cys Thr Ala Ser Cha ProPro Gln Cys Gln ^(D)Pro^(L)Pro 94 1422.7 159 SEQ ID NO: 159 OctG Cys ThrAla Ser Cha Pro Pro Gln Cys Gln ^(D)Pro^(L)Pro 93 1430.0 160SEQ ID NO: 160 OctG Cys Thr Ala Ser Cha Pro Pro Gln Cys Gln^(D)Pro^(L)Pro 95 1549.6 (4NHCOPhe) 161 SEQ ID NO: 161 hPhe Cys Thr AlaSer OctG Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1473.4 162 SEQ ID NO: 162hPhe Cys Thr Ala Ser Cha Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 95 1457.3163 SEQ ID NO: 163 Nle Cys Thr Ala Ser OctG Pro Pro Gln Cys Tyr^(D)Lys^(L)Glu 95 1374.4 164 SEQ ID NO: 164 Nle Cys Thr Ala Ser Cha ProPro Gln Cys Gln ^(D)Pro^(L)Gln 95 1405.5 165 SEQ ID NO: 165 OctG Cys ThrAla Ser Ile Pro Pro Gln Cys Tyr ^(D)Lys^(L)Glu 95 1488.0 166SEQ ID NO: 166 Nle Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Pro^(L)Ile 95 1385.6 167 SEQ ID NO: 167 Nle Cys Thr Ala Ser Ile ProPro Gln Cys Tyr ^(D)Pro^(L)Phe 95 1419.9 168 SEQ ID NO: 168 Nle Cys ThrAla Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Asp 95 1387.9 169SEQ ID NO: 169 Nle Cys Thr Ala Ser OctG Pro Pro Gln Cys Tyr^(D)Pro^(L)Gln 95 1456.5 170 SEQ ID NO: 170 Nle Cys Thr Ala Ser Cha ProPro Gln Cys Tyr ^(D)Pro^(L)Gln 95 1440.5 171 SEQ ID NO: 171 Nle Cys ThrAla Ser Cha Pro Pro Gln Cys Cha ^(D)Gln^(L)Gln 95 1461.0 172SEQ ID NO: 172 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys Cha^(D)Pro^(L)Gln 95 1430.6 173 SEQ ID NO: 173 hPhe Cys Thr Ala Ser Ile ProPro Gln Cys Tyr ^(D)Pro^(L)Gln 95 1448.6 174 SEQ ID NO: 174 hPhe Cys ThrAla Ser Ile Pro Pro Gln Cys Tyr ^(D)Lys^(L)Glu 95 1480.0 175SEQ ID NO: 175 Nle Cys Thr Ala Ser Cha Pro Pro Gln Cys 2Cl-^(D)Pro^(L)Gln 95 1458.5 Phe 176 SEQ ID NO: 176 Nle Cys Thr Ala Ser ChaPro Pro Gln Cys Gln ^(D)Gln^(L)Gln 95 1555.5 (4NHCOPhe) 177SEQ ID NO: 177 OctG Cys Thr Ala Ser Ile Pro Pro Gln Cys Tyr^(D)Pro^(L)Gln 95 1430.6 178 SEQ ID NO: 178 OctG Cys Thr Ala Ser OctGPro Pro Gln Cys Gln ^(D)Pro^(L)Gln 95 1477.6 179 SEQ ID NO: 179 Nle CysThr Ala Ser Ile Pro Pro Gln Cys Tyr ^(D)Pro^(L)Pro 90 1369.7 180SEQ ID NO: 180 Ile Cys Thr Lys Ser Leu Pro Pro Ile Cys Arg^(D)Pro^(L)Pro 94 1404.8 181 SEQ ID NO: 181 Ile Cys Thr Lys Ser hPhe ProPro Ile Cys Arg ^(D)Pro^(L)Pro 92 1452.6 182 SEQ ID NO: 182 Ile Cys ThrLys Ser Cha Pro Pro Ile Cys Arg ^(D)Pro^(L)Pro 95 1444.6 183SEQ ID NO: 183 Ile Cys Thr Lys Ser Tyr Pro Pro Ile Cys Arg^(D)Pro^(L)Pro 91 1454.5 184 SEQ ID NO: 184 Phe Cys Thr Lys Ser Leu ProPro Ile Cys Arg ^(D)Pro^(L)Pro 95 1438.6 185 SEQ ID NO: 185 Ile Cys ThrLys Ser Leu Pro Pro Arg Cys Arg ^(D)Pro^(L)Pro 95 1447.5 186SEQ ID NO: 186 Ile Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg^(D)Pro^(L)Pro 95 1419.9 187 SEQ ID NO: 187 Ile Cys Thr Lys Ser Leu ProPro His Cys Arg ^(D)Pro^(L)Pro 95 1428.6 188 SEQ ID NO: 188 Ile Cys ThrLys Ser Leu Pro Pro Gln Cys Arg ^(D)Pro^(L)Pro 95 1419.8 189SEQ ID NO: 189 Ile Cys Thr Lys Ser Leu Pro Pro Thr Cys Arg^(D)Pro^(L)Pro 95 1392.4 190 SEQ ID NO: 190 Ile Cys Thr Lys Ser Leu ProPro Arg Cys Lys ^(D)Pro^(L)Pro 95 1420.1 191 SEQ ID NO: 191 Leu Cys ThrLys Ser Leu Pro Pro Lys Cys Arg ^(D)Pro^(L)Pro 95 1420.0 192SEQ ID NO: 192 Nle Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg^(D)Pro^(L)Pro 95 1420.0 193 SEQ ID NO: 193 Cha Cys Thr Lys Ser Leu ProPro Lys Cys Arg ^(D)Pro^(L)Pro 95 1459.7 194 SEQ ID NO: 194 Tyr Cys ThrLys Ser Leu Pro Pro Lys Cys Arg ^(D)Pro^(L)Pro 95 1469.6 195SEQ ID NO: 195 Trp Cys Thr Lys Ser Leu Pro Pro Lys Cys Arg^(D)Pro^(L)Pro 92 1492.6 196 SEQ ID NO: 196 Arg Cys Thr Lys Ser Leu ProPro Lys Cys Tyr ^(D)Pro^(L)Pro 95 1469.6 ^(a))%-purity of compoundsafter prep. HPLC Cys in pos. 2 and 10 in Ex. 1-6, 9-103, 112-131, 133,136-138, 140-141, 143-146, 148-153, 155, 157-196 form a disulfide bridge

2. Biological Methods 2.1. Preparation of the Peptide Samples.

Lyophilized peptides were weighed on a Microbalance (Mettler MT5) anddissolved in sterile water to a final concentration of 1 mM unlessstated otherwise. Stock solutions were kept at +4° C., light protected.

2.2. Enzymatic Assays

Enzyme and substrate conditions were as indicated Table 2.

Kinetic measurements were made in a total reaction volume of 100 μl in96 well flat bottomed plates (Greiner) on a Genios plate reader (Tecan).The enzyme was combined with the peptides (inhibitors) in a buffercontaining 100 mM HEPES (pH 7.5), 50 mM CaCl₂, 0.025% Tween-20, 5% DMSO,and 1 mM of the substrate. The rate of substrate hydrolysis was measuredby monitoring the change in absorbance at 405 nm over 30 minutes toverify linearity of the reaction curve. The average rate from minute 1through minute 10 was used for all calculations. Initial calculations ofbackground subtraction, average rate, duplicate averaging and %inhibition were made using the Magellan software (version 5) from Tecan.IC50% calculations were made using Grafit (version 5.0.10) fromErithacus Software by fitting inhibition data from 6 different inhibitorconcentrations to a 4-parameter equation:

$y = \frac{100\%}{1 + \left( \frac{x}{{IC}_{50}} \right)^{s}}$

In this equation s is the slope factor, x is the inhibitor concentrationand y is % inhibition at a given concentration of the inhibitor.

K_(m)/K_(i) Determination

The K_(m) for the serine protease substrate was determined from aLineweaver-Burke plot (Grafit v5). The values for inhibitors werecalculated using the formula K_(i)=IC50%/(1+([substrate]/K_(m))).

Increasing concentrations of substrate were reacted with the enzyme andthe rate of each reaction (ABS/mSec) was plotted vs. substrateconcentration. The reciprocal plot (Lineweaver-Burke) was also plottedto give K_(m) and V_(max) (inset) (see ref. 1 below).

TABLE 2 Substrate Enzyme concentration concentration Enzyme/Supplier inassay Substrate/Supplier in assay (mM) Elastase from human 0.6mU/reaction N-Met-Ala-Pro-Val-p- 1 neutrophils/Serva nitroanilide/SigmaCathepsinG, from human 1 mU/reaction N-Succinyl-Ala-Pro- 1 neutrophilsPhe-p-nitroanilide CAS nr. 107200-92-0 Sigma Calbiochem Trypsin,Iodination grade, 1 mU/reaction N-Benzoyl-Arg-p- 0.32 from humanpancreas, nitroanilide CAS nr. 9002-07-7 Sigma Calbiochem Chymase, from9 mU/reaction N-Succinyl-Ala-Pro- 1.5 human skin Phe-p-nitroanilideCalbiochem Sigma Thrombin, from Human 100 mU/reactionBenzoyl-Phe-Val-Arg- 0.5 Plasma, high activity, p-nitroanilide CAS nr.9002-04-4 Calbiochem Calbiochem Chymotrypsin, from 1.6 microM/reactionN-Succinyl-Ala-Pro- 1 human pancreas Phe-p-nitroanilide CAS nr 9004-07-3Sigma Calbiochem Coagulation Factor Xa, 0.4 mU/reactionMethoxycarbonyl-D- 2 from uman plasma, Nle-Gly-Arg-p- CAS nr. 9002-05-5nitroanilid Calbiochem Roche Tryptase, from human 12.5 mU/reactionN-Benzoyl-Arg-p- 1.28 lung nitroanilide Calbiochem Sigma Urokinase fromhuman 250 mU/reaction Pyroglu-Gly-Arg-p- 0.5 urine/Sigma Aldrichnitroanilide x HCl CAS nr. 9039-53-6 Endotell Kallikrein, from human0.34 microgram/reaction N-Benzoyl-Pro-Phe- 1 plasma, Arg-p-nitroanilideCAS Nr 9001-01-8 Sigma Calbiochem Plasmin from human 2 mU/reactionD-Val-Leu-Lys-p- 5 plasma, Nitroanilide CAS nr. 9001-90-5 SigmaSigma-Aldrich

2.3. Cytotoxicity Assay

The cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells(CRL-1651) was determined using the MTT reduction assay [see ref. 2 and3, below]. Briefly the method was as follows: HELA cells and COS-7 cellswere seeded at 7.0×10³ and, respectively, 4.5×10³ cells per well andgrown in 96-well microtiter plates for 24 hours at 37° C. at 5% CO₂. Atthis point, time zero (Tz) was determined by MTT reduction (seebelow).The supernatant of the remaining wells was discarded, and freshmedium and the peptides in serial dilutions of 12.5, 25 and 50 μM werepipetted into the wells. Each peptide concentration was assayed intriplicate. Incubation of the cells was continued for 48 hours at 37° C.at 5% CO₂. Wells were then washed once with phosphate buffered saline(PBS) and subsequently 100 μl MTT reagent (0.5 mg/ml in medium RPMI1640and, respectively, DMEM) were added to the wells. This was incubated at37° C. for 2 hours and subsequently the medium was aspirated and 100 μlisopropanol were added to each well. The absorbance at 595 nm of thesolubilized product was measured (OD595peptide). For each concentrationaverages were calculated from triplicates. The percentage of growth wascalculated as follows: (OD595peptide-OD595Tz-OD595Emptywell)/(OD595Tz-OD₅₉₅Empty well)×100% and was plotted for each peptideconcentration. The LC 50 values (Lethal Concentration, defined as theconcentration that kills 50% of the cells) were determined for eachpeptide by using the trend line function of EXCEL (Microsoft Office2000) for the concentrations (50, 25, 12.5 and 0 μM), the correspondinggrowth percentages and the value −50, (=TREND(C50:CO₃%50:%0,-50)).

The GI 50 (Growth Inhibition) concentrations were calculated for eachpeptide by using a trend line function for the concentrations (50, 25,12.5 and 0 μg/m1), the corresponding percentages and the value 50,(=TREND (C50:Co,%50:%o,50).

2.4. Hemolysis

The peptides were tested for their hemolytic activity against human redblood cells (hRBC). Fresh hRBC were washed three times with phosphatebuffered saline (PBS) by centrifugation for 10 min at 2000 ×g. Peptidesat a concentration of 100 μM were incubated with 20% v/v hRBC for 1 hourat 37° C. The final erythrocyte concentration was approximately 0.9×10⁹cells per ml. A value of 0% and, respectively,. 100% cell lysis wasdetermined by incubation of the hRBC in the presence of PBS alone and,respectively, 0.1% Triton X-100 in H2O. The samples were centrifuged,the supernatant was 20-fold diluted in PBS buffer and the opticaldensity (OD) of the sample at 540 nM was measured. The 100% lysis value(OD₅₄₀H₂O) gave an OD₅₄₀ of approximately 1.3-1.8. Percent hemolysis wascalculated as follows: (OD₅₄₀opeptide/OD₅₄₀H₂O)×100%.

2.5 Plasma Stability

405 μl of plasma/albumin solution were placed in a polypropylene (PP)tube and spiked with 45 μl of compound from a 100 mM solution B, derivedfrom 135 μl of PBS and 15 μl of 1 mM peptide in PBS, pH 7.4. 150 μlaliquots were transferred into individual wells of the 10 kDa filterplate (Millipore MAPPB 1010 Biomax membrane). For “0 minutes controls”:270 μl of PBS were placed in a PP tube and 30 μl of stock solution B wasadded and vortexed. 150 μl of control solution were placed into one wellof the filter plate and served as “filtered control”.

Further 150 μl of control solution were placed directly into a receiverwell (reserved for filtrate) and served as “not-filtered control”. Theentire plate including evaporation lid was incubated for 60 mM at 37° C.Plasma samples (rat plasma: Harlan Sera lab UK, human plasma:Blutspendezentrum Zürich) were centrifuged at least for 2 h at 4300 rpm(3500 g) and 15° C. in order to yield 100 μl filtrate. For “serumalbumin”-samples (freshly prepared human albumin: Sigma A-4327, ratalbumin: Sigma A-6272, all at 40 mg/ml concentration in PBS)approximately 1 hour of centrifugation was sufficient. The filtrates inthe receiver PP plate were analysed by LC/MS as follows: Column: JupiterC18 (Phenomenex), mobile phases: (A) 0.1% formic acid in water and (B)acetonitrile, gradient: 5%-100% (B) in 2 minutes, electrosprayionization, MRM detection (triple quadrupole). The peak areas weredetermined and triplicate values were averaged. The binding wasexpressed in percent of the (filtered and not-filtered time point 0 min)control 1 and 2 by: 100-(100×T_(60/)T₀). The average from these valueswas then calculated.

2.6. Pharmacokinetic study (PK)

Pharmacokinetic Study After Single Oral (Gavage) and IntravenousAdministration in Rats

Pharmacokinetic study after single intravenous (i.v.) and oral (p.o.,gavage) administration was performed for the compound of Example 75(“Ex. 75”). 332 g (±10 g) male Wistar mice obtained from RCC Ltd,Laboratory animal Services, CH-4414 Füllinsdorf, Switzerland were usedin the study. The vehicle, physiological saline, was added to give afinal concentration of 2.5 mg/ml of the compound. The volume was 2 ml/kgi.v. and 10 ml/kg p.o. and the peptide Ex. 75 was injected to give afinal intravenous dose of 5 mg/kg and an oral dose of 50 mg/kg. Bloodsamples (approx. 0.24 ml) were taken following the schedule below atdifferent time points into heparinized tubes by automated blood samplingusing the DiLab AccuSampler. When a problem occurred during automatedblood sampling, blood was sampled by retro-orbital bleeding under lightisoflurane anesthesia. Samples were taken at the following time points:0, 5 min (only i.v.), 15, 30 min and 1, 2, 4, 8, 16, 24 and 36 (onlyp.o.) hours and added to heparinized tubes. Plasma was removed frompelleted cells upon centrifugation and frozen at 31 80° C. prior toHPLC-MS analysis.

Preparation of the Plasma Calibration Samples

“Blank” rat plasma from untreated animals was used. Aliquots of plasmaof 0.1 ml each were spiked with 50 ng of propranolol (Internal Standard,IS), (sample preparation by solid phase extraction on OASIS® HLBcartridges (Waters)) and with known amounts of Ex. 75 in order to obtain9 μl asma calibration samples in the range 5-2000 ng/ml. The OASIS® HLBcartridges were conditioned with 1 ml of methanol and then with 1 ml of1% NH₃ in water. Samples were then diluted with 400 μl of 1% NH₃ inwater and loaded. The plate was washed with 1 ml of methano1/1% NH₃ inwater 5/95. Elution was performed using 1 ml of 0.1% TFA in methanol.

The plate containing eluates was introduced into the concentrator systemand taken to dryness. The residues were dissolved in 100 μl of formicacid 0.1%/acetonitrile, 95/5 (v/v) and analysed in the HPLC/MS on areverse phase analytical column (Jupiter C18, 50×2.0 mm, 5 μm,Phenomenex), using gradient elution (mobile phases A: 0.1% formic acidin water, B: Acetonitrile; from 5%B to 100%B in 2 min.).

Preparation of Plasma Samples

From each sample 100 μl of plasma were taken for the extraction. If thevolume was less than 100 μl the appropriate amount of “blank” mouseplasma was added in order to keep the matrix identical to thecalibration curve. Samples were then spiked with IS and processed asdescribed for the calibration curve.

Pharmacokinetic Evaluation

PK analysis was performed on pooled data (generally n=2 or 3) using thesoftware PK solutions 2.0™ (Summit Research Service, Montrose, Colo.81401 USA). The area under the curve AUC was calculated by the lineartrapezoidal rule. AUC_((t-oo)) was estimated as Ct/b (b: eliminationrate constant). AUC_((t-oo)) is the sum of AUC_((0-t)) and AUC_((t-oo)).Elimination half-life was calculated by the linear regression on atleast three data points during the elimination phase. The time intervalsselected for the half-life determinations were evaluated by thecorrelation coefficient (r²), which should be at least above 0.85 andmost optimally above 0.96. In case of i.v. administration the initialconcentration at t_(zero) was determined by extrapolation of the curvethrough the first two time points. Finally bioavailability after i.p.administration was calculated from the normalised AUC_((0-oo)) ratioafter i.p. versus i.v. administration.

3.0 Results

The results of the experiments described under 2.2-2.5, above, areindicated in Table 3 herein below.

TABLE 3 Uro- Hemo- Cathepsin Trypsin Chymo- Chymase Thrombin FXa kinaseTryptase Cyto- lysis at G Elastase at trypsin at at at at At toxicity100 IC50 IC50 100 μM at 100 μM 100 μM 100 μM 100 μM 100 μM 100 μMLC₅₀/GI₅₀ μM Ex (nmol) (nmol) % % % % % % % Hela cells % 1 86 >100000    92.6   7.8 0   1.1 5.7 5.7 0  nd 0 2 84 >100000   92   2.9 0   9.2 5.30.9 39.6 nd nd 3 51 >100000   92 0 1   0   4   4   68   100  0 491 >100000   96   1.8 0   0   2.4 5.4 0  100  0 5 56 >100000   92 3 0  0.5 0.2 5.7 74   nd 0 6 ? nd nd nd nd nd nd nd nd nd nd 7 91 1.5 at 10041 12  13.4  0   11.7  1.1  1.5 100    0.2 μM % 8 126  0.8 at 100   74.2  5.6 71.7  nd nd nd nd nd nd μM % 9 105  4.1 at 100   88.1 nd nd nd ndnd nd nd nd μM % 10 75 0.3 at 100   89.9 nd 9.4 nd nd nd nd nd nd μM %11 95  19 at 100   6.5  73.6 12.1  nd nd nd nd nd nd μM % 12 90  3703897 28  12   11   5   12   59.3   59.3 nd 13 100  8.2 at 100   95.0 nd19.9  nd nd nd nd nd nd μM % 14 52 >100000   88 0 42.3  8.7 6   5.4 84.2100  0 15   56.0 >100000     95.0  54.2 12.7  nd nd nd nd 100  0 1666 >100000     90.0  17.9 12.9  nd nd 3.2 nd 94   0.1 17 55 >100000    90.0 16  27.6  0   nd nd 90.4 94   0.1 18 47 >100000   84 25  32.5 0   nd nd 88.3 100  0 19 41 >100000     94.0 0 26.9  11   32   4   85.2100  0 20 48 >100000     97.0 0 44.1  28   25   6.7 nd 100  0 21 97    16.4   95.6   2.6 5   nd nd nd nd nd nd 22 55 >100000    84. 0 98.8 nd nd 5.7  3.8  8 0 23 38 >100000   90 4 60   0   11   9   29   51 0 2471 >100000   97   1.0 1.2 3.5 30   5.1 0  99 nd 25 102  3.2 at   89.3 nd10.0  nd nd nd nd nd nd 100 μM % 26 49 >100000 84   2.2 0   3   6   3.166.4 nd nd 27 48 nd nd nd nd nd nd nd nd nd nd 28 39 >100000 95 32  0  12   6   1   0  nd nd 29 42 nd nd nd nd nd nd nd nd nd nd 30 39  4990098 49  0   2   3   9   nd nd nd 31 34 >100000   98 15  12   10   8  15   76   nd nd 32 52 nd nd nd nd nd nd nd nd nd nd 33 45 nd nd nd nd ndnd nd nd nd nd 34 56 nd nd nd nd nd nd nd nd nd nd 35 54 nd nd nd nd ndnd nd nd nd nd 36 41 nd Nd nd nd nd nd 0   73.3 83 0 37 35 nd nd nd ndnd nd 5   56   92   0.1 38 31 >100000   96 4 1   0   0   1   11   100  039 38 >100000   94 7 0   2   0   2   34   98 0 40 25  >44862   94 19 8   1   3   10   33   97   0.1 41 49 nd nd nd nd nd nd nd nd nd nd 42 46nd nd nd nd nd nd 7   0  87 0 43 77 nd nd nd nd nd nd nd nd nd nd 44 31 >10000   100  24  3   9   9   14   50   67   0.1 45 47 nd nd nd nd ndnd nd nd nd nd 46   87.5 >100000   95 0 10.2  6.9 12.2  5.8 44.1 nd nd47 64  >10000   87 1 8.2 0   9.3 6.3 0  100  0 48 83 >100000   93 3 ndnd nd nd nd nd nd 49 82  >10000   96 0 0   7.9 nd 6.2 30.5 nd nd 5089 >100000   94 0 nd nd nd nd nd nd nd 51 91 >100000   nd nd nd nd nd ndnd nd nd 52 52 >100000   86 0 42.3  8.7 6   5.4 84.2 100  0 5356 >100000   95 54  12.7  nd nd nd nd 63 0 54 66 >100000   90 18  12.9 nd nd 3.2 nd nd nd 55 55 >100000   90 16  27.6  nd nd nd 90.4 94   0.156 47 >100000   84 25  32.5  0   nd nd 88.3 100  0 57 41 >100000   94 026.9  11   32   4   82.2  0 0 58   47.5 >100000   97 0 44.1  28   25  6.7 nd 100  0 59 55 >100000   84 0 98.8  nd nd 5.7  3.8  8 0 6038 >100000   90 4 60   0   11   9   29.4 51 0 61 72 nd nd nd nd nd nd ndnd nd nd 62 69 nd nd nd nd nd nd nd nd nd nd 63 41 >100000   96 11  7  1   0   0   50   87 0 64 45 >100000   87 0 0   2.3 0   3   0  59 0 65 47nd nd nd nd nd nd 1   57   84 0 66 48 nd nd nd nd nd nd nd nd nd nd 6748 nd nd nd nd nd nd nd nd nd nd 68 59 >100000     84.2   4.3 0   5.48.6 4.6 21.3 nd nd 69 68 nd nd nd nd nd nd nd nd nd nd 70 69 nd nd nd ndnd nd nd nd nd nd 71 70 nd nd nd nd nd nd nd nd nd nd 72 87 nd nd nd ndnd nd nd nd nd nd 73 89 >100000   94 0 nd nd nd nd nd nd Nd 7491 >100000   86 >100000      nd nd nd nd nd nd nd 75 86 69.1 at 100   92.6 7.8 at 100 0   1.1 5.7 5.7 0  nd nd μM % μM % 76 nd   71 nd nd ndnd nd nd nd nd nd 77 nd   68 nd nd nd nd nd nd nd nd nd 78 nd   29 nd<4000     nd nd nd nd nd 61 nd 79 nd   66 nd nd nd nd nd nd nd nd nd 80nd   35 nd >20000     nd nd nd nd nd 12 nd 81 61.3 at 100   28 100000  100000    nd 13.1  8.7 nd nd 58 nd μM % 82 nd   18 nd  72.9 nd nd 15.3 nd 44.5 nd nd 83 nd   43 nd 100000    nd nd nd nd nd 12 nd 84 20195    18   10.8 17103   0   20.6  13.3  10.4   4.2  9 nd 85 nd   28 0 >20000     nd 12.6  25.6  nd nd nd nd 86 47 at 100 μM   26 0 >100000      0   10.7  24.8  nd 0  nd nd % 87 nd   37 nd 106977    ndnd nd nd nd 65 nd 88 >100000       18   6.4 4309   0   0.2 3   96    0.673 nd 89 nd   43 nd nd nd nd nd nd nd 51 nd 90 66975     21   5.233074   0   0   5.5 3.5 5  96 nd 91 45 at 100 μM   28  0 48108   4.713.5  19.4  nd nd 79 nd % 92 nd   43 nd nd nd nd nd nd nd 93 nd 93 nd  41 nd nd nd nd nd nd  5.6 100  nd 94 nd   50 nd nd nd nd nd nd nd ndnd 95 38677     24   8.9 33729   0   0   11.3  10.3  0  89 nd 96 21175    15   7.5 15433   0   3.6 0   6.2 0  52 nd 97 >100000       24   9.577431   0   11.6  4.8 11.9  0  100  nd 98 >100000       21 0 38820   0  5.2 0   0   0  78 nd 99 85196     16   30.5 8558   0   0   0   17.4  0 58 nd 100 nd   35 nd nd nd nd nd nd nd 83 nd 101 nd   49 nd nd nd nd ndnd nd nd nd 102 >100000       13  0 4975   0   1.7 0   0.5 0  55 nd103 >100000       18  6.4 4309   0   10.2  3   9.6  0.6 47 nd 104 53.5at 100   34  0 3.1 at 100 μM 0   7.7 6.2 0   0  nd nd μM % % 105 nd   34nd nd nd nd nd nd nd nd nd 106 nd   49 nd nd nd nd nd nd nd nd nd 107 nd  51 nd nd nd nd nd nd nd nd nd 108 nd   31 nd nd nd nd nd nd nd nd nd109 54.1 at 100   33  0  13.8 0.1 0   5.6 nd nd nd nd μM % 110 nd   38nd nd nd nd nd nd nd nd nd 111 nd   46 nd nd nd nd nd nd nd nd nd 112 nd  39 nd nd nd nd nd nd nd 33 nd 113 nd   35 nd nd nd nd nd nd nd nd nd114 nd   47 nd nd nd nd nd nd nd 34 nd 115 nd   38 nd 27751   nd nd ndnd nd 51 nd 116 nd   46  0 39710   nd nd nd nd nd nd nd 117 nd   33 ndnd nd nd nd nd nd 29 nd 118 nd   43 nd nd nd nd nd nd nd nd nd 119 nd  45 nd nd nd nd nd nd nd nd nd 120 nd   29 nd nd nd nd nd nd nd 38 nd121 11155     18   12.8   27526, IC50 1.2 0   5.6 5.7  4.6 49 nd (nmol)122 35134     18 19   58000, IC50 6.4 0   19.6  11.1   0.2 29 nd (nmol)123 35203     14   7.9   14995, IC50 0   2.7 0   7.6 nd nd nd (nmol) 124nd   40 nd nd nd nd nd nd nd 40 nd 125 18269     15   28.3 >20000, IC504.8 0   0   nd nd 37 nd (nmol) 126 nd   36 nd nd nd nd nd nd nd nd nd127 64 at 100 μM   29  0  47.2 1.9 3.7 13.3  nd 0  nd nd % 128 nd   40nd nd nd nd nd nd nd nd nd 129 nd   30 nd nd nd nd nd nd nd nd nd 130 nd  29 nd nd <4000      nd nd nd nd nd nd 131 45   28  0 nd 46108     ndnd nd nd nd nd 132 nd   26 nd nd nd nd nd nd nd nd nd 133 nd   26 nd ndnd nd nd nd nd nd nd 134 nd   23 nd nd nd nd nd nd nd nd nd 135 nd   23nd nd nd nd nd nd nd nd nd 136 >100000       21  0  67.9 0   5.2 0   0  0  nd nd 137 66975     21   5.2  68.7 0   0   5.5 3.5 5  nd nd 13843856     19   12.2  77.1 4.6 17.1  12.6  14.4  0  nd nd 139 nd   18 ndnd nd nd nd nd nd nd nd 140 20195     18   10.8  79.6 0   20.6  13.3 10.4   4.2 nd nd 141 63.4 at 100   18  0  72.9 0   0   15.3  nd 44.5 56nd μM % 142 nd   16 nd nd nd nd nd nd nd nd nd 143 28 at 100 μM %   1512 91  0   12   0   8   18   nd nd 144 21175       7.5   7.5  80.6 0  3.6 0   6.2 0  nd nd 145 nd   14 nd nd nd nd nd nd nd nd nd 146  1 at100 μM %   12  3 87  0   11   1   0   22   nd nd 147 nd   11 nd nd nd ndnd nd nd nd nd 148 52 at 100 μM %   11  9 91  7   32   8   12   30   ndnd 149 nd   11 nd nd nd nd nd nd nd nd nd 150 nd   10 nd nd nd nd nd ndnd nd nd 151 nd   10 nd nd nd nd nd nd nd nd nd 152 nd    9 nd nd nd ndnd nd nd nd nd 153 56 at 100 μM %     8.5  8 84  0   16   11   16   9 nd nd 154 27 at 100 μM %     8.3  0 4 0   7   0   1   15   nd nd 155 52at 100 μM %     8.2 18 83  3   19   9   12   30   nd nd 156 46 at 100 μM%     7.5  0 5 0   17   0   7   15   nd nd 157 nd    7 nd nd nd nd nd ndnd nd nd 158 55 at 100 μM %     7.1  8 93  0   2   1   10   13   nd nd159 nd    7 nd nd nd nd nd nd nd nd nd 160 55 at 100 μM %    6  3 94 2   23   1   14   30   nd nd 161 nd    6 nd nd nd nd nd nd nd nd nd 162nd     12.5 nd nd nd nd nd nd nd nd nd 163 nd   24 nd nd nd nd nd nd ndnd nd 164 nd   24 nd nd nd nd nd nd nd nd nd 165 nd   22 nd nd nd nd ndnd nd nd nd 166 nd   18 nd nd nd nd nd nd nd nd nd 167 35134     18 19 60.2 6.4 0   19.6  11.1   0.2 nd nd 168 11155     18   12.8  72.9 1.20   5.6 5.7  4.6 nd nd 169 20295     18   10.8  79.6 0   20.6 13.3 10.4   4.2 nd nd 170 nd   16 nd nd nd nd nd nd nd nd nd 171 nd   13 ndnd nd nd nd nd nd nd nd 172 nd   13 nd nd nd nd nd nd nd nd nd 173 nd  12 nd nd nd nd nd nd nd nd nd 174 56 at 100   12  7 85  0   11   3  1   10   nd nd μM % 175 nd   12 nd nd nd nd nd nd nd nd nd 176 69 at 100    10.3  7 55  2   15   1   8   17   nd nd μM % 177 54 at 100    7  586  3   17   7   12   15   nd nd μM % 178 nd    6 nd nd nd nd nd nd ndnd nd 179 nd   50 >100000,  76.0 nd nd nd nd 0  nd nd IC50 (nmol) 180120  nd 60 nd nd nd nd nd <100     nd nd 181 127  nd 113  nd nd nd nd nd40   nd nd 182 111  nd 59 nd nd nd nd nd 39   nd nd 183 243  nd 146  ndnd nd nd nd 25   nd nd 184 221  nd 48 nd nd nd nd nd 27   nd nd 185 514 nd 126  nd nd nd nd nd 14   nd nd 186 337  nd 99 nd nd nd nd nd 15   ndnd 187 158  nd 39 nd nd nd nd nd <100     nd nd 188 105  nd 34 nd nd ndnd nd <100     nd nd 189 164  nd 39 nd nd nd nd nd <100     nd nd 1901500  nd 172  nd nd nd nd nd <100     nd nd 191 400  nd 66 nd nd nd ndnd 21   nd nd 192 650  nd 72 nd nd nd nd nd 16   nd nd 193 431  nd 35 ndnd nd nd nd 6  nd nd 194 1570  nd 431  nd nd nd nd nd 9  nd nd 195 4000 nd 108  nd nd nd nd nd 12   nd nd 196 2165  nd 70 nd nd nd nd nd 52   ndnd Nd: not determined

The results of the experiment described in 2.5 above are indicated inTable 4 herein below.

TABLE 4 Ex. Stability human Plasma t_(1/2) (min) Stability rat Plasmat_(1/2) (min) 22 300 300 23 300 300 75 300 300 121 300 300 158 300 300

The results of the experiment described in 2.6 (PK), above, areindicated in Table 5 herein below.

TABLE 5 Administration route Intravenous Oral Dose (mg/kg) 5 50Dose_(norm) (mg/kg) 5 5 AUC_(0-t) (ng · h/ml) 6044 782 AUC_(0-∞) (ng ·h/ml) 6047 813 AUC_(0-∞ norm) (ng · h/ml) 6047 81 T_(max observed)(hours) 10752 464 T_(max norm) (hours) 10752 46 C_(max norm) (ng/ml)0.08 0.25 β (hours⁻¹) Terminal t_(1/2) (hours) 0.5 0.87 Vd (ml/kg) 5471008 % absorbed (F) 100% 1.3% (percentage of normalized AUC_(0-∞) po.against normalized AUC_(0-∞) i.v.)

The large inter-individual variation in plasma concentration of Ex. 75was most pronounced after single oral administration (1 or i.v.:%C.V=6-68%, except for one value at the lowest measurable concentration173%; for p.o. %C.V.: 113-173%).

Intravenous Administration

After intravenous administration of Ex. 75 at a dose level of 5 mg/kgbody weight, Ex. 75 followed intravenous kinetic characteristics. AfterPK analysis, Ex 75 showed an extrapolated C_(initial) of 14069 ng/ml anda C_(max) observed of 10762 ng/ml at 5 min (0 083 hour). Plasma levelsrapidly decreased to 5774 and 3455 ng/ml at 15 min and 30 min,respectively. From 1 to 2 hours plasma levels decreased with a terminalt_(1/2) of 0.46 hours to 18 ng/ml at 4 hours. The AUC_(0-t) andAUC₀-infinite amounted to 6044 and 6047 ng×h/ml, respectively; theinitial distribution volume amounted to 355 ml/kg. The apparentdistribution volume was 547 ml/kg.

Oral Administration

Alter oral administration of Ex 75 at a dose level of 50 mg/kg bodyweight, plasma levels of Ex. 75 followed oral kinetic characteristics.After PK analysis, Ex. 75 showed an observed C_(max) of 464 ng/ml at0.25 hour (15 min). From 0.25 hours, plasma levels decreased with aterminal t_(1/2) of 0.87 hours to 24 ng/ml at 4 hours. The AUC_(0-t) andAUC_(0-infinite) amounted to 782 and 813 ng×h/ml. respectively. Takinginto account the absorption of 1.3%, the apparent distribution volumewas 1008 ml/kg.

Oral Versus Intravenous Administration

Due to the different dose levels between the oral group versus the i.v.group, values were compared after dose normalisation.

Compared to the normalized AUC_(0-infinite) value after i.v.administration of Ex. 75 (100%: 6047 ng-h/ml), the percentage of Ex. 75absorbed (F) after oral administration amounted to 1.3% (81 ng×h/ml) atan about 234 times lower normalised C_(max) value after oraladministration (46 versus 10762 ng/ml; Table 3). The apparentdistribution volume after oral administration was about 1.8 fold higherthan after i.v. administration (1008 versus 547 ml/kg).

REFERENCES

1. Barrtt, A. J. Methods in Enzymology 1981, 80, 561-565; Leatherbarrow,R. J. 1992, GraFit, Erithacus Software Ltd., Staines, U.K.

2. Mossman T. J. Immunol.Meth. 1983, 65:55-63

3. Berridge M V, Tan A S. Arch. Biochem. Biophys. 1993, 303:474-482

1-62. (canceled)
 63. A compound of the general formula (I)

wherein

is a dipeptide made up of two different amino acid building blocks, thedipeptide being ^(D)Pro-^(L)Pro(5RPhe), ^(D)Ala-^(L)Pro,^(D)Ile-^(L)Pro, ^(D)Pro-^(L)Leu, ^(D)Pro-^(L)Glu, ^(D)Ala-^(L)Asp,^(D)Asn-^(L)Pro, ^(D)Thr-^(L)Pro, ^(D)Asp-^(L)Pro, ^(D)Phe-^(L)Pro,^(D)Arg-^(L)Pro, ^(D)Ser-^(L)Pro, ^(D)Val-^(L)Pro, ^(D)Pic-^(L)Pro,^(D)Pro-^(L)Asp, ^(D)Pro-^(L)Phe, ^(D)Pro-^(L)Gln, ^(D)Pro-^(L)Ser.^(D)Pro-^(L)Val, ^(D)Thr-^(L)Thr, ^(D)Lys-^(L)Glu, ^(D)Phe-^(L)Thr,^(D)Ala-^(L)Pro, ^(D)Pro-^(L)Ile, or ^(D)Gln-^(L)Gln, and Z is anundecapeptide chain made up of eleven amino acid residues, in which P1is selected from Phe, Nle, OctG, or hPhe; P2 is Cys; P3 is Thr; P4 isselected from Lys or Ala; P5 is Ser; P6 is selected from Asp, Ile, OctG,or Cha; P7 is Pro; P8 is selected from Pro or Pro(4NHCOPhe); P9 isselected from Ile or Gln; P10 is Cys; and P11 is selected from Ser, Tyr,Gln, Cha, or 2Cl-Phe; two residues of Cys, which are present as the P2and P10 residues, being linked by a disulfide bridge formed byreplacement of the two —SH groups by one —S—S— group, in free from or ina pharmaceutically acceptable salt form.
 64. The compound according toclaim 63, in which in the said undecapeptide chain P1 is Phe; P2 is Cys;P3 is Thr; P4 is Lys; P5 is Ser; P6 is Asp; P7 is Pro; P8 is Pro; P9 isIle; P10 is Cys; and P11 is Ser.
 65. The compound according to claim 63,in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 isThr; P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln;P10 is Cys; and P11 is Tyr.
 66. The compound according to claim 63, inwhich the template is ^(D)Pro-^(L)Pro(5RPhe), ^(D)Ala-^(L)Pro,^(D)Ile-^(L)Pro, ^(D)Pro-^(L)Leu, ^(D)Pro-^(L)Glu, ^(D)Ala-^(L)Asp,^(D)Asn-^(L)Pro, or ^(D)Thr-^(L)Pro, and in which in the saidundecapeptide chain P1 is Phe; P2 is Cys; P3 is Thr; P4 is Lys; P5 isSer; P6 is Asp; P7 is Pro; P8 is Pro; P9 is Ile; P10 is Cys; and P11 isSer.
 67. The compound according to claim 63, in which the template is^(D)Asp-^(L)Pro, ^(D)Phe-^(L)Pro, ^(D)Arg-^(L)Pro, ^(D)Ser-^(L)Pro,^(D)Val-^(L)Pro, ^(D)Pic-^(L)Pro, ^(D)Pro-^(L)Asp, ^(D)Pro-^(L)Phe,^(D)Pro-^(L)Gln, ^(D)Pro-^(L)Ser. ^(D)Pro-^(L)Val, ^(D)Thr-^(L)Thr,^(D)Lys-^(L)Glu, ^(D)Phe-^(L)Thr, ^(D)Ala-^(L)Pro, or ^(D)Pro-^(L)Ile,and in which in the said undecapeptide chain P1 is Nle; P2 is Cys; P3 isThr; P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln;P10 is Cys; and P11 is Tyr.
 68. The compound according to claim 63, inwhich the template is ^(D)Lys-^(L)Glu, and in which in the saidundecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 isSer; P6 is OctG; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 isTyr.
 69. The compound according to claim 63, in which the template is^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle;P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 isPro; P9 is Gln; P10 is Cys; and P11 is Gln.
 70. The compound accordingto claim 63, in which the template is ^(D)Lys-^(L)Glu, and in which inthe said undecapeptide chain P1 is OctG; P2 is Cys; P3 is Thr; P4 isAla; P5 is Ser; P6 is Ile P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys;and P11 is Tyr.
 71. The compound according to claim 63, in which thetemplate is ^(D)Pro-^(L)Gln, and in which in the said undecapeptidechain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is OctG;P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 72. Thecompound according to claim 63, in which the template is^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle;P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 isPro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 73. The compound accordingto claim 63, in which the template is ^(D)Gln-^(L)Gln, and in which inthe said undecapeptide chain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala;P5 is Ser; P6 is Cha; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; andP11 is Cha.
 74. The compound according to claim 63, in which thetemplate is ^(D)Pro-^(L)Gln, and in which in the said undecapeptidechain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha;P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Cha.
 75. Thecompound according to claim 63, in which the template is^(D)Pro-^(L)Gln, and in which in the said undecapeptide chain P1 ishPhe; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro;P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Tyr.
 76. The compoundaccording to claim 63, in which the template is ^(D)Lys-^(L)Glu, and inwhich in the said undecapeptide chain P1 is hPhe; P2 is Cys; P3 is Thr;P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln; P10 isCys; and P11 is Tyr.
 77. The compound according to claim 63, in whichthe template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptidechain P1 is Nle; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha;P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is 2Cl-Phe.
 78. Thecompound according to claim 63, in which the template is^(D)Gln-^(L)Gln, and in which in the said undecapeptide chain P1 is Nle;P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 is Cha; P7 is Pro; P8 isPro(4NHCOPhe); P9 is Gln; P10 is Cys; and P11 is Gln.
 79. The compoundaccording to claim 63, in which the template is ^(D)Pro-^(L)Gln, and inwhich in the said undecapeptide chain P1 is OctG; P2 is Cys; P3 is Thr;P4 is Ala; P5 is Ser; P6 is Ile; P7 is Pro; P8 is Pro; P9 is Gln; P10 isCys; and P11 is Tyr.
 80. The compound according to claim 63, in whichthe template is ^(D)Pro-^(L)Gln, and in which in the said undecapeptidechain P1 is OctG; P2 is Cys; P3 is Thr; P4 is Ala; P5 is Ser; P6 isOctG; P7 is Pro; P8 is Pro; P9 is Gln; P10 is Cys; and P11 is Gln. 81.An enantiomer of the compound of formula I as defined in claim
 63. 82. Apharmaceutical composition comprising the compound according to claim 63and a pharmaceutically acceptable carrier.
 83. The pharmaceuticalcomposition according to claim 82 in a form suitable for oral, buccal,rectal, vaginal, topical, transdermal, transmucosal, pulmonary,injection, inhalation, or implantation administration.
 84. Thepharmaceutical composition according to claim 82 in form of a tablet, adragee, a capsule, a lozenge, a pill, a powder, a liquid, a solution, asyrup, an elixir, a slurry, a suspension, an emulsion, a gel, a cream,an ointment, a plaster, a spray, a nebulizer, an inhaler, aninsufflator, a suppository, a sustained-release system, a long actingformulation, a depot preparation, or a liposome.
 85. A method fortreating a disease by inhibiting a protease enzyme in a subject in needthereof, the method comprising administering an effective amount of thecompound of claim 63 to said subject.
 86. The method according to claim85, wherein said inhibition treats an infection in a healthy subject orslows the progression of an infection in an infected subject.
 87. Themethod according to claim 85, wherein the protease enzyme is CathepsinG.
 88. The method according to claim 85, wherein the protease enzyme iselastase.
 89. The method according to claim 85, wherein the proteaseenzyme is tryptase.
 90. The method of claim 85, wherein the disease isselected from the group consisting of cancer, an inflammatory disease,an infection, a cardiovascular disease, an immunological disease, aneurodegenerative disease, and a pulmonary disease.
 91. A process forthe manufacture of a compound according to claim 63 which processcomprises (a) coupling an appropriately functionalized solid supportwith an appropriately N-protected derivative of that amino acid which inthe desired end-product is in position 5, 6 or 7, any functional groupwhich may be present in said N-protected amino acid derivative beinglikewise appropriately protected; (b) removing the N-protecting groupfrom the product thus obtained; (c) coupling the product thus obtainedwith an appropriately N-protected derivative of that amino acid which inthe desired end-product is one position nearer the N-terminal amino acidresidue, any functional group which may be present in said N-protectedamino acid derivative being likewise appropriately protected; (d)removing the N-protecting group from the product thus obtained; (e)repeating steps (c) and (d) until the N-terminal amino acid residue hasbeen introduced; (f) coupling the product thus obtained with a compoundof the general formula

wherein

is as defined in claim 63 and X is an N-protecting group; (g) removingthe N-protecting group from the product obtained in step (f); (h)coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in the desired end-product is inposition 11, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (i) removing the N-protecting group from the product thusobtained; (j) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is one position farther away from position 11, anyfunctional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (k) removing theN-protecting group from the product thus obtained; (l) repeating steps(j) and (k) until all amino acid residues have been introduced; (m)optionally, selectively deprotecting one or several protected functionalgroup(s) present in the molecule and appropriately substituting thereactive group(s) thus liberated; (n) optionally, forming an interstrandlinkage between side-chains of appropriate amino acid residues atpositions 2 and 10; (o) detaching the product thus obtained from thesolid support; (p) cyclizing the product cleaved from the solid support;(q) removing any protecting groups present on functional groups of anymembers of the chain of amino acid residues and, optionally, anyprotecting group(s) which may in addition be present in the molecule;and (r) optionally, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.
 92. A modification of the process according to claim91 for the manufacture of an enantiomer of the compound of formula (I),in which enantiomers of all chiral starting materials are used.
 93. Aprocess for the manufacture of a compound according to claim 63 whichprocess comprises (a′) coupling an appropriately functionalized solidsupport with a compound of the general formula

wherein

is as defined in claim 63 and X is an N-protecting group; (b′) removingthe N-protecting group from the product obtained in step (a′); (c′)coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in the desired end-product is inposition 11, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (d′) removing the N-protecting group from the product thusobtained; (e′) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is one position farther away from position, any functionalgroup which may be present in said N-protected amino acid derivativebeing likewise appropriately protected; (f′) removing the N-protectinggroup from the product thus obtained; (g′) repeating steps (e′) and (f′)until all amino acid residues have been introduced; (h′) optionally,selectively deprotecting one or several protected functional group(s)present in the molecule and appropriately substituting the reactivegroup(s) thus liberated; (i′) optionally, forming an interstrand linkagebetween side-chains of appropriate amino acid residues at positions 2and 10; (j′) detaching the product thus obtained from the solid support;(k′) cyclizing the product cleaved from the solid support; (l′) removingany protecting groups present on functional groups of any members of thechain of amino acid residues and, optionally, any protecting group(s)which may in addition be present in the molecule; and (m′) optionally,converting the product thus obtained into a pharmaceutically acceptablesalt or converting a pharmaceutically acceptable, or unacceptable, saltthus obtained into the corresponding free compound of formula I or intoa different, pharmaceutically acceptable, salt.
 94. A modification ofthe process according to claim 93 for the manufacture of an enantiomerof the compound of formula (I), in which enantiomers of all chiralstarting materials are used.